Antenatal Screening and Diagnosis, Population and Cascade screening

SEE ALSO PRENATAL DIAGNOSIS in PREGNANCY TOPIC BELOW-

1979 Brock DJ, Hayward C. Methylumbelliferyl-guanidinobenzoate reactive proteases and prenatal diagnosis of cystic fibrosis. Lancet 1979; i: 1245-1246. [PubMed]
The titration of trypsin like proteases in cell free amniotic fluid against an artificial substrate, 4methylumbelliferyl-guanidinobezoate which had been proposed as a means of antenatal diagnosis by Nadler et al (Lancet 1980; ii: 96-97; Nadler HL, Walsh MMJ. Pediatrics 1980; 66:690-692. [PubMed]) looked hopeful but could not be reproduced in other centres resulting in an unacceptable number of false negative and false positive results (Tummler B et al. Clin Chem Acta 1982; 125:219-232.[PubMed])

1983 Carbens NJB, Gosden G, Brock DJH. Microvillar peptidase activity in amniotic fluid: possible use in prenatal diagnosis of cystic fibrosis. Lancet 1983; i: 329-331. [PubMed]
The activities of two amniotic fluid peptidases were significantly depressed in the second trimester amniotic fluid supernatant in the presence of a fetus affected by cystic fibrosis. Eventually David Brock, of Edinburgh, used monoclonal antibody specific for isoenzyme of alkaline phosphatase (see below). Eventually both methods were superseded by superior DNA based methods.

1983 Brock DJH. Amniotic fluid alkaline phosphatase isoenzymes in early prenatal diagnosis of cystic fibrosis. Lancet 1983; ii: 941-943. [PubMed]

Antenatal diagnosis in families with a known CF child was possible by assay of the microvillus enzymes at 17-18th week of pregnancy. In pregnancies with a CF fetus there was a profound deficiency of one form of alkaline phosphatase (the phenylalanine-inhibitable form). When phenylalanine and homoarginine were used to define the alkaline phosphatase isoenzymes in stored amniotic fluid, 9 out of 10 cases of CF were identified (Brock DH et al, Hum Genet 1984; 65: 248-251; Brock DH et al, Hum Genet 1988; 78:271-275).
David Brock later (1993) commented that assay of microvillar enzymes in the second trimester amniotic fluid supernatant had a rational physiological basis and had stood the test of time but eventually it was superseded by superior DNA-based methods.

1985 Brock DJH, Befgood D, Barron L, Haward C. Prospective prenatal diagnosis of cystic fibrosis. Lancet 1985; I: 1175-1178.[PubMed]
An immunoassay based on monoclonal antibodies with specificity for the three major isoenzymes of alkaline phosphatase (ALP) was used in second-trimester prenatal diagnosis of cystic fibrosis. When prospective and retrospective data were summed the sensitivity of the test was 91% (39 of 43) and the false-positive rate 6% (5 of 81). The authors concluded that this was probably an acceptable form of prenatal diagnosis of CF for the high-risk mother at the time.

Professor David Brock (figure) of Edinburgh pioneered antenatal diagnosis prior to the identification of the probes in close proximity to the CF gene in 1985. He had previously made major contributions to the antenatal recognition of spina bifida.

1986 Farrell M, Law HY, Rodeck CH, Warren R, Stanier P, Super M, Lissens W, Scambler P, Watson E, Wainwright B, et al. First-trimester prenatal diagnosis of cystic fibrosis with linked DNA probes. Lancet 1986; i: 1402-1405. [PubMed]
More accurate antenatal diagnosis using the new linked probes was described in 1985. Linkage analysis with cloned gene probes has shown that the mutation causing cystic fibrosis was located in the middle of the long arm of chromosome 7. In this paper first-trimester diagnosis of cystic fibrosis is reported in four informative families and second-trimester diagnosis in one family with fetal DNA prepared from chorionic villi, hybridised with the tightly linked DNA probes, pJ3.11 and met. Risk calculations show that the expected false-negative and false-positive rates are approximately 2% and 6%, respectively, for typical nuclear families with one affected living child.

The authors considered existing probes to be sufficiently informative now to allow full diagnosis in about two-thirds of couples presenting with at least one affected child. In half of the remainder, the inheritance of one parental mutant chromosome could be deduced.

1989 Handyside AH, Pattinson JK, Penketh RJ, Delhanty JD, Winston RM, Tuddenham EG. Biopsy of human preimplantation embryos and sexing by DNA amplification. Lancet 1989; 1 (8634):347-349. [PubMed]

The first biopsy of a rabbit embryo had been performed in 1968 (Gardner RL, Edwards RG. Control of the sex ratio at full term in the rabbit by transferring sexed blastocysts. Nature 1968; 218:346-349). In this present paper Handyside and colleagues from the Hammersmith Hospital, London, reported the first unaffected child born following preimplantation genetic diagnosis for an X-linked disorder. A single cell was removed through a hole in the zona pellucida from each of 30 human embryos at the 6-10 cell stage three days after in vitro fertilisation. A normal proportion developed (37%) to the blastocyst stage and six hatched from the zona. Each male embryo was sexed from DNA amplification of a repeated sequence specific for the Y chromosomes. In 15 embryos with the normal two pronuclei the sex was also determined by in situ hybridisation. >
Although at this stage not performed for CF, this technique of pre-implantation genetic diagnosis, was to prove a major advance for some CF carrier couples at high risk of having a CF infant, as it provided an alternative to prenatal diagnosis and termination if the fetus was affected – a course of action which was understandably unacceptable to many couples. The technique was first used for CF in 1992 (Handyside et al, 1992 below).

1992 Handyside AH, Lesko JG, Tarin JJ, Winston RM, Hughes MR. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. N Engl J Med 1992; 327:905-909. [PubMed]

Preimplantation genetic diagnosis of cystic fibrosis was attempted in three couples, both members of which carried the delta F508 deletion. In vitro fertilisation techniques were used to recover oocytes from each woman and fertilize them with her husband’s sperm. Three days after insemination, embryos in the cleavage stage underwent biopsy and removal of one or two cells for DNA amplification and analysis. Only two oocytes from one woman were fertilized normally; DNA analysis of one of the embryos failed and cystic fibrosis was diagnosed in the other (i.e. it was homozygous for delta F508), so neither was transferred. The oocytes of each of the other two women produced non-carrier, carrier, and affected embryos. Both couples chose to have one non-carrier embryo and one carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes.

This is the first report of preimplantation genetic diagnosis to identify the delta F508 deletion causing cystic fibrosis using in vitro fertilisation, biopsy of a cleavage-stage embryo, and amplification of DNA from single embryonic cells (also Handyside et al, 1988 above). Subsequent reports indicated an approximately 30% chance of a successful pregnancy after such an embryo had been implanted.

1992 Mennie ME, Gilfillan A, Compton M, Curtis L, Liston WA, Pullen I, Whyte DA, Brock DJH. Prenatal screening for cystic fibrosis. Lancet 1992; 340:214-216. [PubMed]
This is the first report of antenatal couple screening for CF in the Edinburgh maternity hospitals. Of 4348 women, 14% declined prenatal screening and 13% were not screened for other reasons. Amongst 3165 women there were 111 carriers detected of whom four had carrier partners and all 4 couples opted for prenatal diagnosis. One pregnancy with an affected fetus was terminated. The importance of adequate counselling was stressed.

Antenatal screening for CF became routine in Edinburgh but was eventually discontinued in 2005 for various reasons including the improving prognosis for CF and also the introduction of neonatal screening in Scotland (also Brock 1985 above; Livingstone et al, 1994 below). National antenatal CF carrier screening had not been introduced in the UK by 2018 although accepted in principle by the UK National Screening Committee and recommended in a Health Technology Assessment (Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J. Screening for cystic fibrosis. Health Technol Assess 1999; 3(8):1-104.[PubMed]. Free full text).

1994 Super M, Schwarz MJ, Malone G, Roberts T, Haworth A, Dermody G. Active cascade screening for carriers of cystic fibrosis gene. BMJ 1994; 308:1462-1467. [PubMed]

Dr Maurice Super (1936-2006)  (figure) first encountered CF in Windhoek in South West Africa (Namibia) in 1967 where he started a CF clinic. He subsequently became a leading geneticist and paediatrician in the UK working in Manchester. He was a major protagonist of carrier screening in the extended families of people with cystic fibrosis – so-called “cascade screening”.
The present paper describes 15 carrier couples detected out of 1563 relatives of people with CF who were tested; eight had prenatal tests and three pregnancies were terminated. An average of 16 people per family had been tested. Cascade screening was acceptable to relatives, particularly on the mother’s side of the family and 10 times more successful in detecting carrier couples than unfocused screening.
The genetic testing of all child-bearing relatives of a person with CF is now provided by the UK NHS if the individuals wish to be tested.

1994 Livingstone J, Axton RA, Gilfillan A, Mennie M, Compton M, Liston WA, Liston WA, Calder AA, Gordon AJ, Brock DJ. Antenatal screening for cystic fibrosis: a trial of the couple model. BMJ 1994; 308:1459-1462. [PubMed]
The second report of antenatal screening of 8536 couples in Edinburgh. 8.4% were “ineligible”, 1900 declined screening for various reasons and 5922 (69.4%) were screened. There were four positives (i.e. both partners were CF carrier heterozygotes) and all four couples opted for prenatal diagnosis. There were three terminations where the fetus was affected and one couple elected to have the CF infant. There was 99% satisfaction by those screened.

Antenatal CF screening was pioneered in Edinburgh by David Brock and his colleagues and this is one of the first reports (also Mennie et al, 1992 first report above). Screening was introduced into the two Edinburgh trial hospitals following this report. However, the service was eventually discontinued in 2005 soon after neonatal CF screening was introduced into Scotland. As the outlook for CF improved parental attitudes changed to antenatal diagnosis and termination, also the mutations tested were differed from the neonatal ones, and finally funding for both antenatal and neonatal screening was inadequate. It has been estimated from various studies that for every CF fetus detected by antenatal screening the cost is between £50K and £100K.

1996 Brock DJH. Prenatal screening for cystic fibrosis: 5 years’ experience reviewed. Lancet 1996; 347:148-150. [PubMed]
Antenatal screening had been available at two maternity clinics in Edinburgh, UK, since January, 1992, first on a research basis and then routinely. 25,000 couples had been screened. The take-up rates for the two-step and couple models of delivery were very similar at about 70%. Of 22 high-risk couples identified entirely through screening, 20 (91%) opted for prenatal diagnosis. Four couples returned for second and two for third monitored pregnancies. In all eight cases where affected fetuses were identified, pregnancy was terminated.

David Brock concluded that “these data remove one of the few remaining obstacles to a general implementation of prenatal screening for CF”. However, although prenatal screening was recommended in the UK by a Health Technology Assessment (Murray et al, 1999) and after this was accepted in principle by the National Screening Committee, prenatal screening had not been introduced in the UK by 2018. Furthermore, antenatal CF screening was discontinued in the Edinburgh hospitals in 2005 on grounds of both cost and also the introduction of neonatal screening and the evidence of improving prognosis for infants with CF diagnosed soon after birth (also Mennie et al, 1992 above; Livingstone et al, 1994 above). This seems to have been a definite retrograde step.

However, although prenatal screening was recommended in the UK by a Health Technology Assessment (Murray et al, 1999) and after this was accepted in principle by the National Screening Committee, prenatal screening had not been introduced in the UK by 2012. Furthermore, antenatal CF screening was discontinued in the Edinburgh hospitals in 2005 on grounds of both cost and also the introduction of neonatal screening and the evidence of improving prognosis for infants with CF diagnosed soon after birth (also Mennie et al, 1992 above; Livingstone et al, 1994 above).

1998 Cunningham S, Marshall T. Influence of five years of antenatal screening on the paediatric cystic fibrosis population in one region. Arch Dis Child 1998; 78:345-348. [PubMed]
The incidence of CF in the five years before and after antenatal screening was introduced in Edinburgh decreased from 4.6 to 1.6 infants per year – a reduction greater than could be accounted for by prenatal diagnosis and termination.

–   Much of the early work on antenatal screening during the Eighties was done in Edinburgh by David Brock and his colleagues (Brock 1992; Livingstone et al. 1994; Brock, 1996 all above). It is disappointing that the antenatal screening which Brock pioneered was eventually abandoned in Edinburgh and has not been introduced elsewhere in the UK. The introduction of neonatal CF screening in Scotland and the steady improvement in prognosis, being two reasons given for withdrawal of the antenatal screening in Edinburgh. Financial reasons prevented introduction in England.

Murray J, Cuckle H, Taylor G, Littlewood J, HewisonJ Screening for cystic fibrosis. Health technology Assessment 1999; Vol. 3:No 8. [PubMed]

The authors of this HTA report considered the evidence supported the following actions –

• Antenatal genetic screening should be offered routinely
• Pre-conceptional genetic screening should be made available for couples who request it
• Genetic screening should be available for infertile men and for sperm donors
• Testing should be undertaken in laboratories with an annual throughput of at least 5000 CF tests
• Health authorities should consider introducing neonatal screening

 – After a strong national campaign by the UK CF Trust, neonatal CF screening was agreed by the Health Minister at the time, Yvette Cooper, (against the advice of the National Screening Committee!) in 2001 and became available countrywide by 2007. Preconceptional and antenatal genetic screening is still not routinely available in 2019 except for relatives of a person with cystic fibrosis.

2000 Dudding T, Wilcken B, Burgess B, Hambly J, Turner G. Reproductive decisions after neonatal screening identifies cystic fibrosis. Arch Dis Child Fetal 2000; 82:F124-127. [PubMed]
The extensive New South Wales experience of neonatal CF screening from 1981 to 1996 indicated that two thirds of women who had a CF infant chose to avoid having another child with CF. In subsequent pregnancies 66% had antenatal diagnosis of whom 69% terminated or would have terminated had the fetus been affected. The 59% who decided against further pregnancies did so to avoid having a further child with CF.

As was also shown in East Anglia UK and Brittany France, the presence of a neonatal CF screening programme appears to have an overall effect of reducing the future incidence of CF in the newborns in that region. A similar effect was shown following the introduction of antenatal screening in Edinburgh (Cunningham S, Marshall T. Arch Dis Child 1998; 78:345-348. above [PubMed]). Similar findings re. antenatal diagnosis and termination were reported in the large neonatal CF screening programme from Brittany (Scotet et al, 2000 above [PubMed]). However, it may be that with the steadily improving prognosis termination will become increasingly unacceptable to potential parents. This was said to be one factor in discontinuing the successful antenatal CF screening in Edinburgh.

2002 González-González MC, García-Hoyos M, Trujillo MJ, Rodríguez de Alba M, Lorda-Sánchez I, Díaz-Recasens J, Gallardo E, Ayuso C, Ramos C. Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenat Diag 2002; 22:946-948. [PubMed]
Detection of a single-gene disorder such as a fetal paternally inherited Cystic Fibrosis mutation (Q890X) in maternal plasma at 13 weeks.

2003 Simon-Bouy B, Satre V, Ferec C, Malinge MC, Girodon E, Denamur E, Leporrier N, Lewin P, Forestier F, Muller F. French Collaborative Group. Hyperechogenic fetal bowel: a large French collaborative study of 682 cases. Am J Med Genet 2003; Part A. 121A:209-213. [PubMed]                                                                                                                                                                                                                                                 Hyperechogenic fetal bowel is detected in 0.1-1.8% of pregnancies during the second or third trimester. This 1997-1998 multicenter study in 22 molecular biology laboratories identified 682 cases of hyperechogenic fetal bowel detected by routine ultrasound examination during the second (86%) or third trimester. The fetal bowel was considered hyperechogenic when its echogenicity was broadly similar to, or greater than, that of the surrounding bone. Karyotyping, screening for viral infection, and screening for cystic fibrosis mutations were performed in all cases. Pregnancy outcome and postnatal follow-up were obtained in 656 of the 682 cases (91%). In 447 cases (65.5%), a normal birth was observed. Multiple malformations were observed in 47 cases (6.9%), a significant chromosomal anomaly was noted in 24 (3.5%), cystic fibrosis in 20 (3%), and viral infection in 19 (2.8%). In utero unexplained fetal death occurred in 1.9% of cases, toxemia in 1.2%, IUGR in 4.1%, and premature birth in 6.2%.

This study demonstrates that this ultrasound sign is potentially associated with medically significant outcomes. Having established that the bowel is hyperechogenic, recommended investigations should include a detailed scan with Doppler measurements, fetal karyotyping, cystic fibrosis screening, and infectious disease screening. After birth, newborns require pediatric examination because a surgical treatment may be necessary. This should be combined with clear counseling of the parents.

This is a very clear and practically useful paper from a large multicentre French study which indicates the significance of hyperechogenic bowel during pregnancy.

2005 Dupuis A, Hamilton D, Cole DE, Corey M. Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing. J Pediatr 2005; 147:312-315. [PubMed]
The overall CF birth rate from 1971-1987 was 1 in 2714 with no increasing or decreasing trend. Beginning in 1988, 1 year before identification of the CF transmembrane conductance regulator gene, estimated CF birth rates followed a linear decline to an estimated rate of 1 in 3608 in 2000. CF birth rates may have stabilized in the last few years, but further decline may occur with implementation of carrier screening in the general population. These results demonstrate the temporal association of genetic testing and declining CF birth rates in Canada.

Both neonatal screening in East Anglia (Green et al,1993 above) and antenatal screening in Edinburgh (Cunningham & Marshall, 1998 above) have been associated with a subsequent reduction in the incidence of CF in newborns in those areas – which perhaps is not surprising. We have also noted this in Leeds where neonatal screening has been routine in half the city since 1975 and citywide since 1995

2006 Saker A, Benachi A, Bonnefont JP, Munnich A, Dumez Y, Lacour B, Paterlini-Brechot P. Genetic characterisation of circulating fetal cells allows non-invasive prenatal diagnosis of cystic fibrosis. Prenatal Diagnosis 2006; 26:906-916. [PubMed]
The purpose of this study from Paris was to develop a molecular method to characterise both paternal and maternal CFTR alleles in DNA from circulating fetal cells (CFCs) isolated by ISET (isolation by size of epithelial tumour/trophoblastic cells). This protocol was validated in 12 pregnant women, at 11 to 13 weeks of gestation, whose offspring had a 1 in 4 risk of CF. Results showed that one fetus was affected, seven were heterozygous carriers of a CFTR mutation, and four were healthy homozygotes. These findings were consistent with those obtained by chorionic villus sampling (CVS).

– This test affords a reliable method prenatal diagnosis for high risk couples and avoids the risks associated iatrogenic miscarriage with chorionic biopsy (also note Fetal DNA detected at 13 weeks of a Q890X carrier fetus by Gonzalez-Gonzalez MC et al. Prenatal diagnosis 2002; 22:946-948. [PubMed]).

2007 Massie J, Forbes R, Dusart D, Bankier A, Delatycki MB. Community-wide screening for cystic fibrosis carriers could replace newborn screening for the diagnosis of cystic fibrosis. J Paediatr Child H 2007; 43:721-723. [PubMed]
Most babies with cystic fibrosis (CF) are born to parents who did not know they were carriers until their baby was diagnosed with CF, usually by newborn screening. It is only after the birth of their first child with CF that couples are offered genetic counselling and reproductive choices. Most use this information for prenatal testing of subsequent pregnancies. With the high uptake of first trimester screening for Down syndrome (80% in Victoria, Australia) most couples have had screening during the CF affected pregnancy. Yet screening for CF carrier status is available, costs are similar to that for Down syndrome screening and CF carrier screening only ever needs to be done once. Waiting for couples to have a baby with CF before they are identified as carriers denies them choice. A national policy on CF carrier screening in Australia, and determination to equitably fund such a programme, is required. > Although neonatal screening for CF has been introduced into many countries. There is now the means of identifying CF carrier parents which has been available for the last two decades and the feasibility of antenatal CF screening has been shown by the first studies from Edinburgh in the UK where such screening was pioneered by the late David Brock (Mennie ME et al. Lancet 1992; 340:214-216. [PubMed]).  Also antenatal screening was recommended in a UK Health Technology Assessment in 1999 (Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J. Screening for cystic fibrosis. Health Technol Assess 1999;3(8). [PubMed]) and even agreed by the UK National Screening Committee but not introduced because of the cost (£50K – £100K for each affected fetus detected) and the lack of the necessary counselling services.

2009 Massie J, Petrou V, Forbes R, Curnow L, Ioannou L, Dusart D, Bankier A, Delatycki M. Populations based carrier screening for cystic fibrosis in Victoria: the first three years experience. Aus NZ J Obstet Gynaecol 2009; 49:484-489.[PubMed]
CF carrier screening was offered to 3020 women and couples planning a pregnancy, or in early pregnancy, through obstetricians and general practitioners in Victoria, Australia from January 2006 to December 2008. Of the nine carrier couples, six were pregnant at the time of screening (five natural conception and one in vitro fertilisation) and all had CVS examination performed (mean gestation 12.5 weeks). Two fetuses were affected, three were carriers and one was not a carrier. Termination of pregnancy was undertaken for the affected fetuses. The authors concluded that carrier screening for CF by obstetricians and general practitioners by cheek swab sample can be successfully undertaken prior to pregnancy or in the early stages of pregnancy.

–   Carrier screening was pioneered by David Brock in Edinburgh but abandoned there apparently as a result of the introduction of neonatal screening becoming available and the prognosis improving. However, antenatal screening has been recommended by a UK Health Technology Assessment report, by the UK National Screening Committee but not implemented on the grounds of expense. Indeed it certainly seems to be an approach which should be available to future parents should they wish it. A downward trend in the incidence of CF has been noted in northeastern Italy where antenatal screening is available (Castellani et al, 2009.[PubMed] ).

2009 Christie LM, Ingrey AJ, Turner GM, Proos AL, Watts GE. Outcomes of a cystic fibrosis carrier testing clinic for couples. M J Australia 2009; 191:499-501. [PubMed]
To review the outcomes of offering carrier testing for cystic fibrosis (CF) to couples considering pregnancy, and to women in early pregnancy and their partners. An after-hours clinic was established in Newcastle for discussion of issues related to prenatal testing. Couples were offered CF carrier testing by extracting DNA from a mouthwash sample.  An expanded one-step model was used with both partners being tested initially for the p.F508del cystic fibrosis transmembrane conductance regulator gene (CFTR) mutation. If one partner was a p.F508del carrier, the other partner was tested for an additional 28 CFTR mutations.   Of 1000 individuals who were offered CF carrier testing, none declined. No re-collections of mouthwash samples were required, and results were available within 14 days. There were 730 individuals who had no family history of CF (73%); 27 were carriers (4%; 95% CI, 2.4%-5.3%), and there were two high-risk couples where both partners were carriers of p.F508del. There were 270 individuals who had an affected family member with CF or a child identified as a CF carrier through newborn screening; 126 were carriers (46%; 95% CI, 40.6%-52.8%), and there were two high-risk couples – one couple where both partners were carriers of p.F508del, and another couple where the woman was homozygous for p.F508del and the man was a p.F508del carrier. The information on carrier status led the four high-risk couples to change their reproductive decisions to avoid having a child with CF.

The authors concluded that CF carrier testing for couples using an expanded one-step model will detect about 80% of high-risk couples and enables various reproductive choices. They believe that all couples considering pregnancy, and women in early pregnancy and their partners, should be offered CF carrier testing

This writer agrees with the authors – CF carrier screening should be available to all couples intending to have children.

2010 Scotet V, Dugueperoux I, Audrezet MP, Audebert-Bellanger S, Muller M, Blayau M, Ferec C. Focus on cystic fibrosis and other disorders evidenced in fetuses with sonographic finding of echogenic bowel: 16-year report from Brittany, France. Am J Obstet Gynecol 2010; 203:592. e1-6.[PubMed] Based on the long experience of a region where CF is frequent (Brittany, France), the authors describe disorders diagnosed in fetal echogenic bowel fetuses and assess ultrasonography ability in detecting cystic fibrosis in utero. They reviewed the cases of fetal echogenic bowel diagnosed in pregnant women living in Brittany and referred for CFTR gene analysis over the 1992-2007 period (n = 289). A disorder was diagnosed in 32. 2% of the fetuses, cystic fibrosis being the most commonly identified (7. 6%). They also found digestive malformations (7. 0%), chromosomal abnormalities (3. 7%), and maternofetal infections (3. 7%). Combining these data with their ongoing newborn screening program since 1989 showed that ultrasonography enabled diagnosis of 10. 7% of the cystic fibrosis cases. This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis

This paper reports valuable extensive experience from France indicating the clinical significance of the finding of an echogenic bowel at antenatal ultrasound

2010 Handyside AH. Preimplantation genetic diagnosis after 20 years. Reproductive Biomedicine Online. 2010; 21:280-282. [PubMed]
Alan Handyside observes that preimplantation genetic diagnosis (PGD) should not be an option only for the few couples at risk of serious genetic conditions who can afford it. he considers  appear to have lost sight of the original driving force behind the development of PGD, which is that most couples who carry a serious genetic disorder find it more acceptable to choose to conceive with healthy embryos tested in-vitro at preimplantation stages of development within the first week following fertilization, even if that means discarding those diagnosed as affected.

It has been shown, using cystic fibrosis as an example, that the cost savings to the US health care system of providing free IVF-PGD to all carrier couples compared to the lifetime costs of medical treatment for patients affected by this disease, run to dozens of billions of dollars. With the increasing emphasis in medicine on early diagnosis and prevention of disease together with the availability of new molecular genetic diagnostic tools, a national IVF-PGD programme seems to be the next step in modern health care.

–   The point is well made that “most couples who carry a serious genetic disorder find it more acceptable to choose to conceive with healthy embryos tested in-vitro at preimplantation stages of development within the first week following fertilization even if that means discarding those diagnosed as affected”.   It is likely that his logical suggestion will be taken up eventually – finances and religion permitting. Population screening seems to be a low priority of the UK National Screening Committee.

2010 Castellani C, Macek M Jr, Cassiman JJ, Duff A, Massie J, ten Kate LP, Barton D, Cutting G, Dallapiccola B, Dequeker E, Girodon E, Grody W, Highsmith EW, Kääriäinen H, Kruip S, Morris M, Pignatti PF, Pypops U, Schwarz M, Soller M, Stuhrman M, Cuppens H. Benchmarks for cystic fibrosis carrier screening: a European consensus document. J Cyst Fibros. 2010 May;9(3):165-78. doi: 10.1016/j.jcf.2010.02.005. Epub 2010 Apr 2. [PubMed]Free full text
This paper presents an overview of the conclusions from an international conference convened to address current issues related to the provision of Cystic Fibrosis carrier screening within Europe. Consensus was not aimed at stating whether such a programme should be implemented. Instead the focus was to provide a framework for countries and agencies who are considering or planning its establishment. The general principles and target population of Cystic Fibrosis carrier screening, advantages and disadvantages, health economics, monitoring and future evaluative and research directions were covered. A range of screening strategies have been assessed and compared: pre-conceptional and prenatal screening; individual and couple screening; sequential and simultaneous sampling or testing. Furthermore, technical issues were examined with respect to the choice of the panel of mutations, its detection rate, sensitivity, management of intermediate ‘at-risk’ couples, screening approach to different populations and ethnic minorities, and assurance of laboratory quality control. The consensus statement also aims to establish the benchmarks for communicating with health care providers, the general public and potential and actual participants before and after the genetic test.

– A very detailed and informative article

Bruni T, Mameli M, Pravettoni G, Boniolo G. Cystic fibrosis carrier screening in Veneto (Italy): an ethical analysis. Med Health Care Philos. 2012 Aug;15(3):321-8. doi: 10.1007/s11019-011-9347-7.[PubMed]
A recent study by Castellani et al. (JAMA 302(23):2573-2579, 2009) describes the population-level effects of the choices of individuals who underwent molecular carrier screening for cystic fibrosis (CF) in Veneto, in the northeastern part of Italy, between 1993 and 2007. The authors discuss some of the ethical issues raised by the policies and individual choices that are the subject of this study. In particular, (1) they discuss the ethical issues raised by the acquisition of genetic information through antenatal carrier testing; (2) they consider whether by choosing to procreate naturally these couples can harm the resulting child and/or other members of society, and what the moral implications of such harm would be; (3) they consider whether by choosing to avoid natural procreation carrier couples can harm current or future individuals affected by cystic fibrosis; (4) they discuss whether programs that make carrier testing available can be considered eugenic programs.

–   This article discusses some of the arguments against population and antenatal screening.

2013 Dugueperoux I. Audrezet MP. Parent P. Audebert-Bellanger S. Roussey M. Ferec C. Scotet V. Cascade testing in families of carriers identified through newborn screening in Western Brittany (France). J Cyst Fibros 2013; 12:338-44. [PubMed]
Report a unique assessment of family testing following the identification of carriers by NBS for over 20 years, in an area where CF is frequent. The authors reviewed all of the carriers identified by NBS between 1991 and 2010 and registered the tests done in those families.  Newborn screening identified 0.1% of the newborns as carriers, which correspond only to 2.6% of the expected carriers born within the period, and 1/3 of those with an increased IRT level. Of the 195 families, 75.9% requested testing (2.5 tests per family). The authors identified 183 carriers and five 1-in-4 risk couples. Reassurance about genetic status was provided to 96% of the couples.

–   The authors concluded that carriers detected by newborn screening appeared to be well managed in their area, and cascade testing that informs on genetic status seems relatively active.

Wayne W Grody, Barry H Thompson, Anthony R Gregg, Lora H Bean, Kristin G Monaghan, Adele Schneider, Roger V Lebo       ACMG position statement on prenatal/preconception expanded carrier screening.  Genet Med. 2013 Jun;15(6):482-3.doi: 10.1038/gim.2013.47. Epub 2013 Apr 25. [PubMed]

For years, clinicians have offered gene-by-gene carrier screening to patients and couples considering future pregnancy or those with an ongoing pregnancy early in gestation. Examples include ethnic-specific screening offered to Ashkenazi Jewish patients and pan-ethnic screening for cystic fibrosis and spinal muscular atrophy.
Next-generation sequencing methods now available permit screening for many more disorders with high fidelity, quick turnaround time, and lower costs. However, instituting these technologies carries with it perils that must be addressed. The basis for the selection of disorders on expanded carrier screening panels should be disclosed. The information provided about disorders with mild phenotypes, variable expression, low penetrance, and/or characterized by an adult onset should be complete and transparent, allowing patients to opt out of receiving these test results. Patients also must be made aware of the concept of residual risk following negative test results. Laboratories have a duty to participate in and facilitate this information transfer.

Wayne W Grody is Professor in the Departments of Pathology & Laboratory Medicine, Pediatrics, and Human Genetics  UCLA School of Medicine, Los Angeles, California

2014 Archibald AD. Massie J. Smith MJ. Dalton DG. du Sart D. Amor DJ.  Population-based genetic carrier screening for cystic fibrosis in Victoria. J Aust 2014; 200(4):205-6. [PubMed]
(No summary available)

2014 Cunningham F. Lewis S. Curnow L. Glazner J. Massie J. Respiratory physicians and clinic coordinators’ attitudes to population-based cystic fibrosis carrier screening. J Cyst Fibros 2014; 13(1):99-105. [PubMed]
Attitudes of Australian CF healthcare professionals toward population-based cystic fibrosis carrier screening were examined. A purpose-designed questionnaire was distributed to 111 respiratory physicians and 30 CF clinic coordinators throughout Australia. Seventy-one questionnaires (52 physicians and 19 coordinators (46.8%, 63.3% respectively)) were returned. Forty respondents (56.3%) supported population-based carrier screening for CF. Support for screening was associated with rating the factors: carrier risk being 1 in 25 (OR 1.72 (1.12, 2.65)), reassurance when both partners test negative (OR 1.67 (1.12, 2.46)) and the daily treatment regimen for CF patients (OR 1.59 (1.05, 2.42)) as important. Opposition to screening was associated with identifying potential discrimination against carriers as a disadvantage (OR 0.3 (0.12, 0.88)), and limitations of predicting clinical outcomes as a barrier (OR 0.46 (0.25, 0.83)).

–   So there is moderate support for population-based carrier screening for CF by Australian CF healthcare professionals. They consider the perceived barriers to implementation are surmountable which is encouraging.

2014 Delatycki MB, Burke J, Christie L, Collins F, Gabbett M, George P, Haan E, Ioannou L, Martin N, McKenzie F, O’Leary P, Scoble-Williams N, Turner G, Massie J. Human genetics society of Australasia position statement: population-based carrier screening for cystic fibrosis. Hum Genet 2014; 17:578-83. [PubMed]
Since the discovery in 1989 of mutations in cystic fibrosis transmembrane conductance regulator (CFTR) it has been possible to identify heterozygous mutation carriers at risk of having affected children. The Human Genetics Society of Australasia has produced a position statement with recommendations in relation to population-based screening for CF. These include: (1) that screening should be offered to all relatives of people with or carriers of CF (cascade testing) as well as to all couples planning to have children or who are pregnant; (2) the minimum CFTR mutation panel to be tested consists of 17 mutations which are those mutations that are associated with typical CF and occur with a frequency of 0.1% or higher among individuals diagnosed with CF in Australasia; (3) that genetic counselling is offered to all couples where both members are known to have one or two CFTR mutations and that such couples are given the opportunity to meet with a physician with expertise in the management of CF as well as a family/individual affected by the condition.

–    This is a clear recommendation from the Human Genetics Society of Australasia that screening for CFTR mutations be offered to both to known carriers but also to all couples either planning pregnancies or in early pregnancy. The first report of antenatal couple screening for CF in the Edinburgh maternity hospitals (Mennie ME et al. Lancet 1992; 340:214-216. [PubMed]) described 4348 women, 14% declined prenatal screening and 13% were not screened for other reasons. Amongst 3165 women there were 111 carriers detected of whom four had carrier partners and all 4 couples opted for prenatal diagnosis. One pregnancy with an affected fetus was terminated. The importance of adequate counselling was stressed. Antenatal screening for CF then became routine in Edinburgh (where it had been pioneered by the late David Brock) but surprisingly it was eventually discontinued in 2005 for various reasons including the introduction of neonatal screening in Scotland and the improving prognosis for CF. Also national antenatal CF carrier screening had not been introduced in the UK by 2015. Although antenatal screening had been accepted in principle by the UK National Screening Committee having been recommended in a Health Technology Assessment (Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J. Screening for cystic fibrosis. Health Technol Assess 1999; 3(8):1-104.[PubMed]. Free full text) The high cost of providing genetic counselling was stated as the main reason for not introducing it; still not introduced in 2018.

–    This reviewer considers that failure to provided pre-conceptional and antenatal carrier screening in the UK must now be regarded as suboptimal health care and a major missed opportunity.[Please see also Topics section on ‘Diagnosis’ where more of the early papers are reviewed]

2014 Higgins AS. Flanagan JD. Von Wald T. Hansen KA. Preconception cystic fibrosis screening in infertile couples using an expanded carrier screening test. Obstet Gynecol 2014; 123 Suppl 1:97S. [PubMed]
The American College of Obstetricians and Gynecologists recommends offering preconception and prenatal screening to all couples for cystic fibrosis, whereas the American College of Medical Genetics also recommends screening for spinal muscular atrophy. Both groups suggest specific screening if there is a family or personal history of a genetic disease or if the individual is from a high-risk ethnic group. The purpose of this study was to determine whether availability of a more comprehensive, affordable genetic screening tool increased the number of infertility patients choosing to be screened for cystic fibrosis and other genetic diseases.
This was a retrospective chart review of new infertility patients evaluated between May 2010 and May 2013. These couples had a detailed pedigree and were offered the Counsyl expanded carrier screening test.
Sixteen hundred sixty-nine new infertility couples were offered Counsyl expanded carrier screening. The carrier frequency for cystic fibrosis was 6.8% with 0% of the couples concordant heterozygotes. The carrier frequency for spinal muscular atrophy was 2.51% with 0% of the couples concordant heterozygotes. Fragile X premutation was found in 2.78% (2/72).
The authors concluded with availability of the Counsyl screening test, the percentage of new infertility patients choosing to have preconception genetic screening increased from 2% to 8%. The largest increase (17.5% of new patients) in screening followed the reduction in out-of-pocket expense in May 2012. Infertility patients are in a unique position to investigate their family history, discuss appropriate preconception genetic screening, and, if discovered to be at high risk of a genetic illness, review their reproductive options.

2014 Xue Ioannou L. McClaren BJ. Massie J. Lewis S. Metcalfe SA. Forrest L. Delatycki MB. Population-based carrier screening for cystic fibrosis: a systematic review of 23 years of research. Genet Med 2014; 16(3):207-16. [PubMed]
This review provides a systematic evaluation of the literature from the past 23 years on population-based carrier screening for cystic fibrosis, focusing on the following: uptake of testing; how to offer screening; attitudes, opinions, and knowledge; factors influencing decision making; and follow-up after screening. Recommendations are given for the implementation and evaluation of future carrier-screening programmes.

Suggest see also –
2014 Ioannou L et al. Attitudes and opinions of pregnant women who were not offered cystic fibrosis carrier screening. Eur J Hum Genet 2014; 22(7):859-65. [PubMed]
Majority (80.5%) consider screening should be offered; 49.7% would have liked it in their present pregnancy.

2014 Ioannou L et al. No thanks – reasons why pregnant women declined an offer of cystic fibrosis carrier screening. J Commun Genet 2014; 5(2):109-17. [PubMed]
The main reasons for declining screening were having no family history of CF (58%) and not considering a termination of pregnancy for CF (53%). Providers and consumers should be informed that most children born with autosomal-recessive conditions such as CF have no family history of the condition.

2014 Janssens S. De Paepe A. Borry P. Attitudes of health care professionals toward carrier screening for cystic fibrosis. A review of the literature. J Community Genet 2014; 5(1):13-29. [PubMed]
Eleven studies were retrieved describing the attitudes toward carrier screening for CF. Health care providers state willingness to be involved in a carrier screening program, but there is need for appropriate education as well as adequate support given the time constraints already present in consultation. The prospect of an increasing number of genetic disorders for which screening becomes possible, and the potential increasing demand for such screening in the future calls for the need for further debate on the desirability of carrier screening and relevant questions such as the conditions screened, the providers involved, the information provision, and counselling.

2014 Minkoff H. Berkowitz R. The case for universal prenatal genetic counseling. Obstet Gynecol 2014; 123(6):1335-8.[PubMed]
Scientific advances in human genetics and prenatal diagnostic technologies challenge the counselling infrastructure of most obstetric services. All women, not just those surpassing some poorly defined level of risk, deserve genetic counselling. Approaches for achieving this goal are discussed.

2014 Zvereff VV. Faruki H. Edwards M. Friedman KJ. Cystic fibrosis carrier screening in a North American population. Genetics in Medicine 2014; 16(7):539-4, [PubMed]
The aim of this study was to compare the mutation frequency distribution for a 32-mutation panel and a 69-mutation panel used for cystic fibrosis carrier screening. Patients referred for cystic fibrosis screening from January 2005 through December 2010 were tested using either a 32-mutation panel (n = 1,601,308 individuals) or a 69-mutation panel (n = 109,830). The carrier frequencies observed for the 69-mutation panel study population (1/36) and Caucasian (1/27) and African-American individuals (1/79) agree well with published cystic fibrosis carrier frequencies; however, a higher carrier frequency was observed for Hispanic-American individuals (1/48) using the 69-mutation panel as compared with the 32-mutation panel (1/69). The 69-mutation panel detected ~20% more mutations than the 32-mutation panel for both African-American and Hispanic-American individuals.
The authors concluded that expanded panels using race-specific variants can improve cystic fibrosis carrier detection rates within specific populations. However, it is important that the pathogenicity and the relative frequency of these variants are confirmed.

2014 Massie J, Castellani C, Grody WW.  Carrier screening for cystic fibrosis in the new era of medications that restore CFTR function. Lancet. 2014 Mar 8;383(9920):923-5. doi: 10.1016/S0140-6736(13)61092-2. Epub 2013 Aug 30. Review. No abstract available.  PMID: [PubMed] 
A timely and very interesting review. Unfortunately there is no abstract available so I have summarised the  main messages as follows –

Although the introduction of carrier screening has resulted in a reported reduction in live CF births by 50%, the authors note that its widespread introduction has been limited by several issues including variable phenotype of patients with the same genotype, the numerous mutations associated with cystic fibrosis, low public awareness of the disease, infrastructure for preconception and prenatal care, genetic counseling resources, and health economic considerations. Resolution of these issues has been slow.
Furthermore, a new issue has emerged — namely, the development of CFTR restorative therapy that challenges the idea that cystic fibrosis is not curable. In this article the authors discuss the implications of “CFTR restorative therapy” on carrier screening for cystic fibrosis. These recent developments include a CFTR suppressor that promotes ribosomal read through for patients with nonsense class 1 mutations (ataluren), a CFTR potentiator that promotes chloride channel gating (ivacaftor) and two CFTR correctors that promote trafficking (lumacaftor and VX-661). The licensing of ivacaftor for the treatment of people with the GF551D (Gly551Asp) mutation undoubtedly represents a new era for the treatment of CF. The availability, and dramatic results of ivacaftor treatment for people with one or two Gly551Asp mutations are likely to influence some decisions about whether to terminate an affected pregnancy. If the drugs are shown to work from infancy, some may argue carrier screening in no longer justified; others would consider carrier screening would still be justified so parents could consider their ability to look after a child with CF or alternatively prepare them for the task.
Unfortunately even treatment is started soon after birth there is already definite evidence, in both human and animal CF newborns, of there already being significant structural changes. These include meconium ileus, pancreatic structural changes, absence of the vas deferens and structural airway abnormalities. So then the question arises whether pregnant women could safely take CFTR potentiators, correctors or suppressors to prevent these intrauterine complications. Even if the new drugs were proved safe during pregnancy, preconception population carrier screening would still be needed with prenatal testing to establish the diagnosis so appropriate treatment could be started. Even further speculation into the future would consider the need to included only mutations that were associated with severe disease in any screening programme.

Finally, the very high annual cost of ivacaftor (US$270,000) and of presumably other new CFTR therapies still to come, tend to shift the balance in favour of screening.  The authors note an ethical dilemma that “inclusion of the cost of ivacaftor in cost-effectiveness studies is likely to shift the balance substantially in favour of carrier screening while at the same time, an effective but costly therapy is on offer”.
Noting there is still much information needed and no changes to present carrier programmes are needed, the authors consider the information given to at-risk couples about the Gly551Asp will need to change.

–  This reviewer’s (JML) comments.  While discussing these issues one should not loose sight of the fact that, with present knowledge accumulated over many years of research, it is possible for all couples identified as prospective carrier parents to choose an infant unaffected by CF without the need to terminate any pregnancy at any stage by using preimplantation genetic diagnosis. Cystic fibrosis is now a preventable condition that most parents would wish their child to avoid if at all possible.

John Massie, Liane Ioannou, Martin Delatycki. Prenatal and preconception population carrier screening for cystic fibrosis in Australia: where are we up to? Aust N Z J Obstet Gynaecol   2014 Dec;54(6):503-9.doi: 10.1111/ajo.12255.Epub 2014 Oct 28. [PubMed}

Aims: To describe prenatal and preconception population carrier screening for cystic fibrosis (CF) in Australia and consider progress towards establishing a universal program.
Method: Medline and Embase databases (1989-2013) were searched for all publications with Australian data. Existing programs for CF carrier screening in Australia were reviewed and professional peak body websites accessed to determine recommendations.
Results: Twenty-two studies met the inclusion criteria. Key stakeholder groups believe that prenatal and preconception carrier screening for CF should be available. Health-economic analyses support that CF carrier screening can be cost-effective. There are small programs for CF carrier screening, in Victoria, New South Wales and Queensland. The Human Genetics Society of Australasia (HGSA) specifically recommend that screening be offered to women and couples planning a pregnancy and in the early stages of pregnancy. Other peak bodies indirectly endorse the availability of CF carrier screening. Barriers to screening include not being offered screening, the cost of testing, inequity of access and an incorrect perception that not having a family history of CF lowers risk.
Conclusions: There is support for prenatal and preconception CF carrier screening by the community, health professionals and peak professional bodies in Australia. The barriers to development of a national screening program could be overcome with greater physician engagement and government support.
Implications: In the interest of equity, government funded testing should be routinely offered to all pregnant women and couples planning a pregnancy.

Dr John Massie of the Department of Respiratory Medicine, Royal Children’s Hospital, Parkville, Victoria, Australia; Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, Australia.

2015 Girardet A; Ishmukhametova A; Willems M; Coubes C; Hamamah S; Anahory T; Des Georges M; Claustres M.  Preimplantation genetic diagnosis for cystic fibrosis: the Montpellier center’s 10-year experience.  Clin Genet 2015; 87(2):124-32, 2015 Feb.   [PubMed] 
An overview of 10 years of experience of preimplantation genetic diagnosis (PGD) for cystic fibrosis (CF) in one center. Owing to the high allelic heterogeneity of CF transmembrane conductance regulator (CFTR) mutations in south of France, the authors set up a powerful universal test based on haplotyping eight short tandem repeats (STR) markers together with the major mutation p.Phe508del. Of 142 couples requesting PGD for CF, 76 have been so far enrolled in the genetic work-up, and 53 had 114 PGD cycles performed. Twenty-nine cycles were canceled upon in vitro fertilization (IVF) treatment because of hyper- or hypostimulation. Of the remaining 85 cycles, a total of 493 embryos were biopsied and a genetic diagnosis was obtained in 463 (93.9%), of which 262 (without or with a single CF-causing mutation) were transferable. Twenty-eight clinical pregnancies were established, yielding a pregnancy rate per transfer of 30.8% in the group of seven couples with one member affected with CF, and 38.3% in the group of couples whose both members are carriers of a CF-causing mutation [including six couples with congenital bilateral absence of the vas deferens (CBAVD)]. So far, 25 children were born free of CF and no misdiagnosis was recorded. Our test is applicable to 98% of couples at risk of transmitting CF.

–   As the prognosis and treatment options have improved for people with CF, the decision to terminate an early pregnancy, where the fetus is found to have CF through antenatal diagnosis in the first trimester, becomes an increasingly difficult decision for both parents and professionals.  If the parents have already been identified as CF carriers through population carrier screening, by having had an affected relative or even had previous children with CF, PIGD is an ideal way to avoid having a child with CF. The ability to identify CF carriers to avoid having an affected infant, without having to terminate a pregnancy, does not seem to have received the attention it deserves since the advent of the new mutation specific treatments. Cystic fibrosis is potentially an avoidable condition using available knowledge.  The first birth of a normal girl after in vitro fertilisation and preimplantation diagnostic testing for cystic fibrosis was reported as long ago as 1992 (Handyside AH et al. N Engl J Med 1992; 327(13):905-9. [PubMed]).

2015 Girardet A, Viart V, Plaza S, Daina G, De Rycke M, Des Georges M, Fiorentino F, Harton G, Ishmukhametova A, Navarro J, Raynal C, Renwick P, Saguet F, Schwarz M, SenGupta S, Tzetis M, Roux AF, Claustres M. The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus.  Eur J Hum Genet. 2015 May 27. doi: 10.1038/ejhg.2015.99. [Epub ahead of print] [PubMed]
(Full text available at the Eur J Hum Genet website)
Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries.
On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized in this paper, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented.

–  A very detailed paper to which many of the international experts in this area have contributed – a valuable source of information covering all aspects relating to preimplantation genetic diagnosis.

2015 Hadj Fredj S; Ouali F; Siala H; Bibi A; Othmani R; Dakhlaoui B; Zouari F; Messaoud T Prenatal diagnosis of cystic fibrosis: 10-years experience.  Pathol Biol 2015; 63(3):126-9.  [PubMed]
10 years experience in prenatal diagnosis of cystic fibrosis performed in the Tunisian population. Based on family history, 40 Tunisian couples were selected for prenatal diagnosis. Fetal DNA was isolated from amniotic fluid collected by transabdominal amniocentesis or from chronic villi by transcervical chorionic villus sampling.
Thirteen fetuses were affected, 21 were heterozygous carriers and 15 were healthy with two normal alleles of CFTR gene. Ten couples opted for therapeutic abortion. The microsatellites genotyping showed the absence of contamination of the fetal DNA by maternal DNA in 93.75%. The diagnostic strategy provides rapid and reliable prenatal diagnosis for at risk families.

– The majority (77%) of the, presumably Muslim, couples with an affected fetus opted for termination. With the new treatment options and improving prognosis for people with CF, opting for termination of an affected fetus is an increasingly difficult decision for some couples. The availability of population carrier screening and, if indicated, preimplantation genetic diagnosis would reduce the need for taking these difficult decisions.

2015  Hill M, Twiss P, Verhoef TI, Drury S, McKay F. Mason S, Jenkins L, Morris S, Chitty LS. Non-invasive prenatal diagnosis for cystic fibrosis: detection of paternal mutations, exploration of patient preferences and cost analysis. Prenat Diagn. 2015 Oct;35(10):950-8. doi: 10.1002/pd.4585. Epub 2015 Apr 5 [PubMed] Full version on the internet
The authors aim to develop non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF) and determine costs and implications for implementation. A next-generation sequencing assay was developed to detect ten common CF mutations for exclusion of the paternal mutation in maternal plasma. Using uptake data from a study exploring views on NIPD for CF, total test-related costs were estimated for the current care pathway and compared with those incorporating NIPD.
The assay reliably predicted mutation status in all control and maternal plasma samples. Of carrier or affected adults with CF (n = 142) surveyed, only 43.5% reported willingness to have invasive testing for CF with 94.4% saying they would have NIPD. Using these potential uptake data, the incremental costs of NIPD over invasive testing per 100 pregnancies at risk of CF are £9025 for paternal mutation exclusion, and £26 510 for direct diagnosis.
The authors have developed non-invasive prenatal diagnosis for risk stratification in around a third of CF families. There are economic implications due to potential increased test demand to inform postnatal management rather than to inform decisions around termination of an affected pregnancy. This is important as it  appears treatment should be started soon as possible after birth.

2015 Ioannou L, Delatycki MB, Massie J, Hodgson J, Lewis S.  “Suddenly Having two Positive People who are Carriers is a Whole New Thing”- Experiences of Couples Both Identified as Carriers of Cystic Fibrosis Through a Population-Based Carrier Screening Program in Australia. J Genet Couns. 2015 Dec;24(6):987-1000.  [PubMed]
A population-based CF carrier-screening program was implemented in Victoria, Australia in 2006. This study explored the experiences of couples when both partners were identified as CF carriers. Between January 2006 and December 2010, 10 carrier couples were identified and invited to undertake a semi-structured interview. Nine interviews were conducted, seven couple interviews and two individual interviews. One couple declined to participate due to the recent termination of an affected pregnancy. Interviews were analyzed using inductive content analysis.
All couples experienced surprise on learning their carrier couple result. The couples who were pregnant at the time of screening chose to have prenatal diagnosis, with the majority considering it to be the “next step.” The two couples who had an affected pregnancy reported feelings of devastation and grief upon receiving their prenatal diagnosis result and terminated the pregnancy. All carrier couples were offered free genetic counseling, with only one couple declining the offer. Couples were unprepared for a positive carrier couple result. However, all the couples changed their reproductive behavior as a result of their carrier status.

–   The results of this study have been used to inform the program and service offered to CF carrier couples particularly with respect to genetic counseling for reproductive decision making.

2015 Janssens S, Chokoshvilli D, Binst C, Mahieu I, Henneman L, De Paepe A, Borry P.  Attitudes of cystic fibrosis patients and parents toward carrier screening and related reproductive issues.  Eur J Hum Genet. 2015;24(4):506-12.  [PubMed] 
A written questionnaire was administered to adult patients and parents of children with CF in Belgium with the aim to explore participants’ attitudes toward CF carrier screening and related reproductive issues. The study population was recruited from a CF patient registry in Belgium and comprised 111 participants (64 parents, 47 patients aged 16 or older). More than 80% of all participants were in favour of preconception carrier screening for CF. However, some were concerned over potential negative consequences of population-wide CF carrier screening.
Regarding future reproductive intentions, 43% of the participants indicated a desire to have children. Among these, pre-implantation genetic diagnosis was found to be the most preferred reproductive option, closely followed by spontaneous pregnancy and prenatal diagnosis. Although the findings of the  study suggest that patients and parents of children with CF support a population-based carrier-screening program for CF, they also highlight some issues deserving particular attention when implementing such a program.

–    A number of population-based carrier screening programs are published, usually with the support of people with CF and their relatives.  It is  unfortunate that the recent impressive and very welcome advances in treatment have somewhat overshadowed the fact that CF is now a preventable condition and, since the availability of pre-implantation genetic diagnosis, preventable without the need for termination of any pregnacy.

2015 Jelin AC, Anderson B, Wilkins-Haug L, Schulkin J. Obstetrician and gynecologists’ population-based screening practices. J Matern Fetal Neonatal Med. 2015 Sep 25:1-5. [Epub ahead of print] [PubMed] 
Cross-sectional survey was performed by mailing paper surveys to Fellows of the American College of Obstetricians and Gynecologists and a subset of Fellows who belong to the Collaborative Ambulatory Research Network (CARN).
Response rates were 57% for the CARN network. Almost all responders (92%) offer population-based genetic screening in the prenatal period and almost all (93%) conduct counseling prior to the provision of genetic testing. Almost all (92%) counsel patients when the result is positive, with 46% being the primary counselor and 55% calling the patient themselves. When results are negative, 73% counsel with 58% indicating they are the primary counselor and 17% call patients themselves. A total of 72% have received continuing medical education (CME) on genetics within 5 years, with 79% receiving CME at conferences and 21% receiving CME online.
The authors concluded that Ob-gyns have a large role in providing patients new genetic screening technologies. This role requires a significant knowledge base, some of which can be obtained by online modules; however, their study suggests online education is underutilized as a means for CME on genetic screening among ob-gyns.

2015 Nishida K1, Smith Z, Rana D, Palmer J, Gallicano GI. Cystic fibrosis: A look into the future of prenatal screening and therapy. Birth Defects Res C Embryo Today. 2015 Mar;105(1):73-80. doi: 10.1002/bdrc.21091. [PubMed] 
Despite recent guidelines suggesting prenatal screening for carriers of cystic fibrosis (CF) mutations, many physicians do not offer patients this service or even counseling. Some argue that the risks of miscarriage associated with prenatal diagnostic techniques outweigh the benefit of added insight, but with the advent of newer, noninvasive techniques, risks of miscarriage may be significantly lowered. Prenatal diagnosis provides parents the time to prepare for raising a child with CF, and soon, could provide treatment options in utero that could improve quality of life.
Here, the authors describe two of the most promising gene therapy approaches: lentivirus and adenoassociated virus (AAV)-mediated gene transduction. Thus, prenatal detection and treatment is in a most crucial stage for care of patients with CF.

– It is of some concern that intra uterine gene therapy treatment of a CF fetus is increasingly mentioned in the literature as a possibilty when the birth of such a fetus could be avoided by carrier indentification and preimplantation genetic diagnosis.
– Although scientifically interesting, it is unlikely that anyone would be prepared to undertake intrauterine gene therapy for a human fetus affected by CF in the foreseeable future. However, there have been previous suggestions that fetal gene therapy would be necessary (Larson et al, 1997; Cohen & Larson, 2006 above) although the work on which these suggestions were based was not repeatable in a careful UK study (Buckley et al, 2008 below). Also it is very unlikely that fetal gene therapy would ever be advisable or indeed approved by the regulatory authorities.
– It is unfortunate that there seems to be lessening of interest in both antenatal screening and diagnosis and population screening for CF mutations – these aspects of prevention being overshadowed by the dramatic developments in specific mutational therapy. In this writer’s opinion this is unfortunate for the detection of a CF mutation in each of a couple proposing to have children can, by the use of preimplantation genetic diagnosis, allow them to have a healthy child unaffected by CF.

2015 Zlotogora J, Grotto I, Kaliner E, Gamzu R. The Israeli national population program of genetic carrier screening for reproductive purposes.  Genet Med. 2015 Apr 16. doi: 10.1038/gim.2015.55. [Epub ahead of print] [PubMed]
The Israeli population genetic screening program for reproductive purposes, launched in January 2013, includes all known, nationally frequent severe diseases (carrier frequency 1:60 and/or disease frequency 1 in 15,000 live births). The carrier screening program is free of charge and includes  testing for cystic fibrosis
Data on the tests performed over a 12-month period were collected from laboratories nationwide.  More than 62,000 individuals were tested. The carrier frequency was within the expected range for most of the diseases. The national population genetic carrier screening is aimed toward providing couples with knowledge of the existing options for the prevention of serious genetic conditions when it is relevant for them. It is still too early to determine whether this aim has been achieved.

–   It is encouraging that this service is now available in Israel. The take up by young people before becoming pregnant will be interesting for previous studies have shown only a modest interest amongst non-relatives and non-pregnant individuals of child bearing age..

2015 Turillazzi E, Frati P, Busardò FP, Gulino M, Fineschi V. The European Court legitimates access of Italian couples to assisted reproductive techniques and to pre-implantation genetic diagnosis. Med Sci Law. 2015 Jul;55(3):194-200. doi: 10.1177/0025802414532245. Epub 2014 Apr 28.[PubMed]
On 28 August 2012, the European Court of Human Rights (ECHR) issued a judgment regarding the requirements for the legitimate access of couples to assisted reproductive techniques (ART) and to pre-implantation genetic diagnosis (PGD).
This judgment concerns the case of an Italian couple who found out after their first child was born with cystic fibrosis that they were healthy carriers of the disease. When the woman became pregnant again in 2010 and underwent fetal screening, it was found that the unborn child also had cystic fibrosis, whereupon she had the pregnancy terminated on medical grounds. In order to have the embryo genetically screened prior to implantation under the procedure of PGD, the couple sought to use in vitro fertilisation to have another child. Since article 1 of the Italian law strictly limits access to ART to sterile/infertile couples or those in which the man has a sexually transmissible disease, the couple appealed to the European court, raising the question of the violation of articles 8 and 14 of the European Convention on Human Rights.
The applicants lodged a complaint that they were not allowed legitimate access to ART and to PGD to select an embryo not affected by the disease. The European Court affirmed that the prohibition imposed by Italian law violated article 8 of the European Convention on Human Rights. Focusing on important regulatory and legal differences among EU Nations in providing ART treatments and PGD, the authors derived some important similarities and differences.

2016 Beard CA; Amor DJ; Di Pietro L; Archibald AD. “I’m Healthy, It’s Not Going To Be Me”: Exploring experiences of carriers identified through a population reproductive genetic carrier screening panel in Australia. Am J Med Genet Part A. 2016; 170(8):2052-9. [PubMed]
Advancing genetic testing technologies mean that population-based carrier screening for multiple inherited conditions is now available. As the number of genetic conditions being screened increases, there is a need for research into how people experience these screening programs. This research aimed to explore how women experience simultaneous carrier screening for three inherited conditions: cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS). A qualitative approach was adopted using in-depth semi-structured interviews to explore the experiences of ten female participants: five SMA carriers, three CF carriers, and two FXS premutation carriers. Eight participants were pregnant when offered screening by their general practitioner or obstetrician and the decision to have screening was described as straightforward. Participants reported experiencing emotional responses such as anxiety and stress while waiting for either their partner’s carrier screen result (CF or SMA carriers) or the pregnancy’s CVS result (FXS carrier) and sought additional information about the relevant condition during this time

Most participants were in favour of population carrier screening for these conditions, preferably prior to conception. Genetic counsellors played an essential role in supporting couples after they received a carrier result given the variable consent processes undertaken when screening was offered. Further research should focus on the development of reliable online information tailored to people receiving carrier results and strategies for raising awareness of the availability of population carrier screening within the community.

2016 Castellani C, Picci L, Tridello G, Casati E, Tamanini A, Bartoloni L, Scarpa M, Assael BM. Cystic fibrosis carrier screening effects on birth prevalence and newborn screening. Genet Med. 2016 Feb;18(2):145-51. doi: 10.1038/gim.2015.68. Epub 2015 Jun 18. [PubMed]  
The effects of cystic fibrosis (CF) carrier screening on birth prevalence trends and newborn screening (NBS) efficiency were evaluated by comparing two Italian regions; carrier screening was performed in one region (eastern region (ER)) and not in the other (western region (WR)).  Annual births of infants with CF, NBS false-positive results, NBS uncertain diagnoses (borderline sweat chloride (BSC)), carrier tests performed, and carriers detected were monitored during the 1993-2013 period.

A total of 259 newborns with CF were detected. In the eastern region, 150 carrier couples were found. Mean annual percentage of birth prevalence decrease was 9% per 10,000 (P = 0.002) and was greater in the ER (15%, P = 0.0008; WR 1%, P = ns). The WR estimated birth prevalence was 1/3,589 in 1993 and 1/3,870 in 2013; in the ER it was 1/2,730 in 1993 and 1/14,200 in 2013. The ER birth prevalence correlated inversely with the number of carrier couples (P = 0.0032). The ratio between CF cases and NBS-positive results significantly decreased in the ER (1.6%, P = 0.0001) but not in the WR. The ratio between prevalence of BSC and of CF cases increased in the ER (P = 0.008) but not in the WR (P = 0.1).

Carrier screening was connected with a decrease in birth prevalence of CF. Poorer NBS performance was observed in the carrier screening area

.- An example of how the introduction of CF carrier screening will significantly reduce the incidence of CF in a region. A similar effect has been reported to follow the introduction of general newborn CF screening.

2016  Elsas CR, Schwind EL, Hercher L, Smith MJ, Young KG. Attitudes Toward Discussing Approved and Investigational Treatments for Cystic Fibrosis in Prenatal Genetic Counseling Practice. J Genet Couns. 2016 Jun 9. [Epub ahead of print]  [PubMed]
Most of the genetic counsellors had never heard of ivacaftor or Kalydeco™ prior to taking the survey. Therefore, counsellors need to be better educated about the availability of CFTR mutation-based treatments before they will be able to incorporate discussion of new treatment options into their counseling.

– It is no surprise that most counselors had never heard of ivacaftor. However, the impact of the new treatments will undoubtedly influence prenatal counseling practice. (As we have discussed elsewhere. See also Massie et al Lancet. 2014 Mar 8; 383:923-5. Summarised in the 2015 section).

2016 Fitzgerald C, B. Linnane, E. Heery, N. Conneally, S. George, P. Fitzpatrick.  Newborn bloodspot screening for cystic fibrosis: What do antenatal and postnatal women know about cystic fibrosis? J Cyst Fibros 2016;15(4):436-42. [PubMed]

Newborn bloodspot screening (NBS) for CF was added to the NBS programme in Ireland in July 2011. Little is known about antenatal or postnatal women’s knowledge about CF.This was a cross-sectional study of 662 antenatal (≥36weeks gestation) and 480 postnatal women (post NBS). Women were asked to self-complete a questionnaire including 14 CF knowledge questions. Among the respondents significantly more postnatal than antenatal women were aware that CF is included on the NBS (81.8% vs 63.5%; p<0.001). 92.7% believe that there are health consequences to being a carrier and 33.6% believe there is a cure for CF. In the multivariate analysis, lower educational status, being an antenatal mother, having no family history of CF were associated with poor CF knowledge, while increasing age was found to be protective against poor CF knowledge

The authors suggest the results from this study provide a useful insight into women’s preexisting knowledge about CF, which could be used to inform initial discussions with parents about their child’s diagnosis.

Barry Linnane (figure) is Director of the Cystic Fibrosis Programme and Paediatric Respiratory Consultant, Universty Hospital, Limerick

2016 Franasiak JM; Olcha M; Bergh PA; Hong KH; Werner MD; Forman EJ; Zimmerman RS; Scott RT Jr. Expanded carrier screening in an infertile population: how often is clinical decision making affected?.  Genet Med 2016 Mar 3. doi: 10.1038/gim.2016.8.  [PubMed]

Options for preconception genetic screening have grown dramatically. Expanded carrier screening (ECS) now allows for determining carrier status for hundreds of genetic mutations by using a single sample, and some recommend ECS prior to in vitro fertilization. This study seeks to evaluate how often ECS alters clinical management when patients present for infertility care. All patients tested with ECS at a single infertility care center from 2011 to 2014 were evaluated. The overall rate of positive ECS results and the number of couples who were carriers of the same genetic disorder were evaluated.A total of 6,643 individuals were tested, representing 3,738 couples; 1,666 (25.1%) of the individuals had a positive test result for at least one disorder. In 8 of the 3,738 couples, both members of the couple were positive for the same genetic disorder or had a test result that placed them at risk of having an affected child. Three of eight cases were cystic fibrosis. In this cohort, ECS affected clinical care eight times after 6,643 tests (0.12%, confidence interval: 0.05-0.24%) in 3,738 couples (0.21%, confidence interval: 0.09-0.42%).The authors note that Expanded Carrier Screening is becoming more widespread. In a large case series, ECS affected clinical decision making for patients presenting for infertility care in 0.21% of cases. The authors suggest this information must be weighed when utilizing these tests and may be a helpful part of patient counseling

.- This is data from a selected population of couples attending an infertility clinic but nonetheless interesting and is likely to be the way forward in the future when it will not be acceptable to ignore opportunities to avoid serious inherited disease

Jason Frasaniak (figure) is attending Physician and Laboratory Supervisor – Reproductive Medicine Associates of New Jersey Marlton Office

2016  Guissart, C. Dubucs, C. Raynal, A. Girardet, F. Tran Mau Them, V. Debant, C. Rouzier, A. Boureau-Wirth, E. Haquet, J. Puechberty, E. Bieth, D. Dupin Deguine, P. Khau Van Kien, M.P. Brechard, V. Pritchard, M. Koenig, M. Claustres, M.C. Vincent Non-invasive prenatal diagnosis (NIPD) of cystic fibrosis: an optimized protocol using MEMO fluorescent PCR to detect the p.Phe508del mutation. J Cyst Fibros. 2016 Dec 28. pii: S1569-1993(16)30680-4. doi: 10.1016/j.jcf.2016.12.011. [Epub ahead of print][PubMed]
Analysis of cell-free foetal DNA (cff-DNA) in maternal plasma is very promising for early diagnosis of monogenic diseases; in particular, cystic fibrosis (CF). However, NIPD of single-gene disorders has been limited by the availability of suitable technical platforms and the need to set up patient or disease-specific custom-made approaches.  To make research applications more readily accessible to the clinic, the authors report a simple assay combining two independent methods to determine the presence or absence of paternally inherited foetal allele p.Phe508del (the most frequent mutation in CF patients worldwide).

The first method detects the presence or absence of a p.Phe508del allele by Mutant Enrichment with 3′-Modified Oligonucleotide PCR coupled to Fragment Length Analysis (MEMO-PCR-FLA).   The second method detects the p.Phe508del allele with classical Multiplex Fluorescent PCR including five intragenic and extragenic STR markers of the CFTR locus and a specific SRY sequence.

They collected 24 plasma samples from 23 women carrying foetuses at risk for CF and tested each sample using both methods. Their new procedures were successfully applied to 10 couples where fathers carried the p.Phe508del mutation and mothers were carrying a different mutation in the CFTR gene.  These simple tests provided clear positive or negative results from the maternal plasma of the pregnant women. They confirmed the presence of cff-DNA in the studied samples by the identification of a tri-allelic DNA profile using a miniSTR kit. All results were correlated with chorionic villus sampling or amniocentesis analyses.

The authors concluded this non-invasive prenatal approach, easily set up in any clinical laboratory where prenatal diagnosis is routinely performed, offers many advantages over current methods: it is simple, rapid, and cost-effective. It opens up the possibility for testing a large number of couples with offspring at risk for CF.

2016  Janssens S, Chokoshvilli D, Binst C, Mahieu I, Henneman L, De Paepe A, Borry P. Attitudes of cystic fibrosis patients and parents toward carrier screening and related reproductive issues. Eur J Hum Genet. 2016 Apr;24(4):506-12. [PubMed]
Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder affecting ~1 in 2500-4000 Caucasians. As most CF patients have no family history of the disorder, carrier screening for CF has the potential to prospectively identify couples at risk of conceiving an affected child. At-risk couples may consequently choose to act on the provided information and take steps to avoid the birth of a child with CF. Although carrier screening is widely believed to enhance reproductive autonomy of prospective parents, the practice also raises important ethical questions. A written questionnaire was administered to adult patients and parents of children with CF with the aim to explore participants’ attitudes toward CF carrier screening and related reproductive issues. The study population was recruited from a CF patient registry in Belgium and comprised 111 participants (64 parents, 47 patients aged 16 or older). The authors found that more than 80% of all participants were in favor of preconception carrier screening for CF.However, some were concerned over potential negative consequences of population-wide CF carrier screening. Regarding future reproductive intentions, 43% of the participants indicated a desire to have children. Among these, preimplantation genetic diagnosis was found to be the most preferred reproductive option, closely followed by spontaneous pregnancy and prenatal diagnosis. Although the findings of our study suggest that patients and parents of children with CF support a population-based carrier screening program for CF, they also highlight some issues deserving particular attention when implementing such a program

– It is no surprise that 80% of people familiar with the major problems of CF are in favour of preconception carrier screening. This contrasts with the relative lack of interest in the general population as evidenced by the less than 50% response for cascade carrier screening in most studies.

2016 Dugueperoux I; L’Hostis C; Audrezet MP; Rault G; Frachon I; Bernard R; Parent P; Blayau M; Schmitt S; Genin E; Ferec C; Scotet V. Highlighting the impact of cascade carrier testing in cystic fibrosis families. J Cyst Fibros 2016; 15(4):452-9.  [PubMed]
Cascade carrier testing within cystic fibrosis (CF) affected families offers relatives of CF patients the opportunity to know their status regarding the mutation that segregates within their family, and thus to make informed reproductive choices. As an Australian study has recently shown that this test seemed underused, we searched to assess uptake of this test in a European area where CF is common, and to report its public health implications. METHODS: This study relied on 40 CF-affected families from western Brittany, France. Investigations included drawing of family trees and registration of carrier tests performed in those families.

RESULTS: Of the 459 relatives eligible for testing, 185 were tested, leading to an adjusted uptake rate of testing of 40.7% (95% CI: [34.1%; 47.3%]). The main predictors for having testing were being female (p=0.031) and having a high prior risk (p<0.001). Planning a pregnancy or expecting a child (reported in at least 38.4% of tested relatives) also appeared critical in choosing to be tested. Overall, carrier testing allowed to reassure more than 1/4 of the relatives and to detect five new 1-in-4 at-risk couples who then requested prenatal diagnosis.

CONCLUSIONS: This observational study assesses, for first time in Europe, uptake of CF cascade carrier testing within CF families, which is a critical tool to reassure non-carriers and to detect early new at-risk couples.

–   The take up of carrier testing by eligible relatives is usually a disappointing 40-50% as the this French study.

2016 Kazmerski TM; Gmelin T; Slocum B; Borrero S; Miller E.  Attitudes and Decision Making Related to Pregnancy Among Young Women with Cystic Fibrosis.  Maternal & Child Health Journal.  2016 Aug 16. [PubMed]

In this study from Pittsburgh the number of female patients with CF able to consider pregnancy has increased with improved therapies. This study explored attitudes and decision making regarding pregnancy among young women with CF. Twenty-two women with CF ages 18-30 years completed semi-structured, in-person interviews exploring experiences with preconception counseling and reproductive care in the CF setting. Interviews were audio-recorded, transcribed, and coded using a thematic analysis approach.Participants (9 paediatric, 5 adult and 2 combined CF clinic directors) indicated CF is a major factor in pregnancy decision-making. Although women acknowledged that CF influences attitudes toward pregnancy, many expressed confusion about how CF can affect fertility/pregnancy. Many perceived disapproval from CF providers regarding pregnancy and were dissatisfied with reproductive care in the CF setting.Young female patients with CF reported poor understanding of the effect of CF on fertility and pregnancy and limited preconception counseling in CF care. Improvements in female sexual and reproductive health care in CF are warranted.– One of a number of recent publications from Pittsburgh indicating that despite the perceived fundamental role of CF care providers in CF female sexual and reproductive health care, they face significant barriers. Investment in provider training is needed to better address the complex SRH needs of young female patients

2016 Lazarin GA, Haque IS. Expanded carrier screening: A review of early implementation and literature.
Perinatol. 2016 Feb;40(1):29-34. doi: 10.1053/j.semperi.2015.11.005. Epub 2015 Dec 21. [PubMed]
Carrier screening is the practice of testing individuals to identify those at increased risks of having children affected by genetic diseases. Professional guidelines on carrier screening have been available for more than 15 years, and have historically targeted specific diseases that occur at increased frequencies in defined ethnic populations.

Enabled by rapidly evolving technology, expanded carrier screening aims to identify carriers for a broader array of diseases and may be applied universally (equally across all ethnic groups). This new approach deviates from the well-established criteria for screening models.

– In this review, the authors summarise the rationale for expanded carrier screening using available literature regarding clinical and technical data, as well as provider perspectives. They also discuss important avenues for further research.

2016 Massie J.  Newborn screening and population carrier screening for cystic fibrosis: Two ends of the same rope. J Cyst Fibros. 2016 Jul;15(4):407-8. doi: 10.1016/j.jcf.2016.05.006. Epub 2016 May 31.[PubMed]
In this timely editorial John Massie discuses four papers on this subject in this issue – a subject on which he has extensive practical experience. He notes as CF is inherited more than the affected infants can benefit from the diagnosis.  With access to cascade screening why does anyone have to have their first child with CF to derive these benefits when the same mutation analysis test used for screening is widely available and not all that expensive?The four articles discussed are on maternal knowledge about CF NBS (Fitzgerald et al, 2016), on parental experience of screening (Rueegg et al, 2016), on how families use the information about a family member with CF for cascade carrier testing (Dugueperoux et al, 2016) and the fourth about community based carrier testing and its relevance to NBS (Stafler et al, 2016). These papers are discussed in more detail below.Massie concludes this group of papers on CF NBS and carrier screening demonstrates the value of on going quality improvement, relevant to new programs and existing ones alike. The timeliness of definitive diagnosis by post-NBS including sweat testing and consultation with the CF team is essential to quality care. He suggests further work needs to be done to consider the consent process for NBS. This respects parents’ autonomy and in doing so augments the provision of information that will help a wider knowledge of CF and promote cascade family testing and perhaps population carrier screening. As we move forward we should aim for the best possible CF screening service. Finally CF NBS, cascade carrier testing and population-based screening are a continuum that could well be served by single national programs to offer all people reproductive choices and have those born with CF referred for care sooner. This suggestion is very relevant as many families are not, at present, benefiting from the choices possible with optimal use our existing knowledge

2016 Moran Gal, Khen Khermesh, Michal Barak, Min Lin, Hadas Lahat, Haike Reznik Wolf, Michael Lin, Elon Pras, and Erez Y. Levanon Expanding preconception carrier screening for the Jewish population using high throughput microfluidics technology and next generation sequencing  BMC Med Genomics 2016 ;9(1):24. Free PMC article. [PubMed]
The authors examine the implementation of the combined high-throughput technologies of specific target amplification and next generation sequencing (NGS), for expanding the carrier screening program in the Israeli Jewish population as a test case.They compiled a panel of 370 germline mutations, causing 120 disorders, previously identified in affected Jewish individuals from different ethnicities. This mutation panel was simultaneously captured in 48 samples using a multiplex PCR-based microfluidics approach followed by NGS, thereby performing 17,760 individual assays in a single experiment.The sensitivity (measured with depth of at least 50×) and specificity of the target capture was 98 and 95% respectively, leaving minimal rate of inconclusive tests per sample tested. 97% of the targeted mutations present in the samples were correctly identified and validated.
The authors concluded their methodology was shown to successfully combine multiplexing of target specific primers, samples indexing and NGS technology for population genetic screens. Moreover, it’s relatively ease of use and flexibility of updating the targets screened, makes it highly suitable for clinical implementation.This protocol was demonstrated in pre-conceptional screening for pan-Jewish individuals, but can be applied to any other population or different sets of mutations.

2016 Plantinga M, Birnie E, Abbott KM, Sinke RJ, Lucassen AM, Schuurmans J, Kaplan S, Verkerk MA, Ranchor AV, van Langen IM. Population-based preconception carrier screening: how potential users from the general population view a test for 50 serious diseases. J Hum Genet. 2016 Oct;24(10):1417-23. doi: 10.1038/ejhg.2016.43. Epub 2016 May 11. [PubMed]
To date, preconception carrier screening (PCS) has largely targeted single diseases such as cystic fibrosis, but next generation sequencing (NGS) allows the testing of many genes or diseases simultaneously. The authors have developed an expanded NGS PCS test for couples; simultaneously it covers 50 very serious, early-onset, autosomal recessive diseases that are untreatable.

This is the first, noncommercial, population-based, expanded PCS test to be offered prospectively to couples in a health-care setting in Europe. So far, little is known about how potential users view such a PCS test. They therefore performed an online survey in 2014 among 50 people from the target population in the Netherlands. They enquired about their intention to take an expanded PCS test if one was offered, and through which provider they would like to see it offered.

One-third of the respondents said they would take such a test were it to be offered. The majority (44%) preferred the test to be offered via their general practitioner (GP) and 58% would be willing to pay for the test, with a median cost 75 Euro. They intend to perform an implementation study in which this PCS test will be provided via selected GPs in the Northern Netherlands.

–   This is the way forward although for conditions such as cystic fibrosis there seems to be limited enthusiasm for such a policy.  Lack of knowledge and some religious beliefs are obstacles to progress.

2016 Aviram M, Alkrinawi S, Picard E, Prais D, Steuer G, Inbar O, Kerem E, Blau H.The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening.  J Cyst Fibros. 2016 Jul;15(4):460-6. doi: 10.1016/j.jcf.2015.08.007. Epub 2015 Sep 16.  [PubMed]
Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. The authors sought to evaluate its impact using a retrospective review of governmental databanks, the national CF registry and CF centers.CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 387 couples carrying two mutations who opted for invasive pre-natal diagnosis. 87 pregnancies annually were terminated.  From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population.PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children with CF regularly have significant disease at diagnosis, the authors suggest a balanced approach, utilizing both PCS and newborn screening.

– So a nationally funded population screening programme, but no neonatal screening programme, resulted in unacceptable late diagnosis for those eventually born with CF (at mean age of 6 months) by which time over half had respiratory disease and 20% were infected with P. aeruginosa.

2016 Vears DF, Delany C, Massie J, Gillam L. Parents’ experiences with requesting carrier testing for their unaffected children.  Genet Med. 2016 Mar 24. doi: 10.1038/gim.2016.24. [Epub ahead of print] [PubMed]
International guidelines generally recommend delaying genetic carrier testing in children until the child reaches the age of majority or is mature enough to be involved in the decision. Several studies have shown that carrier testing of children does occur in some instances, particularly in siblings of a child affected with a genetic condition. However, little research has explored parents’ experiences with the testing process, the impact of knowing a child’s carrier status, and whether parents communicate carrier information to their children.Semi-structured interviews were conducted with 33 parents of children who had one of three genetic conditions (cystic fibrosis, haemophilia, and Duchenne muscular dystrophy). Inductive content analysis was used to analyse the data.Eight distinct pathways to carrier testing were distinguishable. While some parents had requested testing, others had been offered testing and some had received carrier results incidentally following testing to exclude affected status. Some parents were discouraged from testing, which led to frustration.

Overall, 67% of the parents had received carrier results for at least one child, and parents were happy to have results, even if their children were carriers. Despite recommendations against carrier testing, this study provides evidence of varying practices and highlights a need to review the guidelines.

– This reviewer disagrees with the advice against carrier testing in the case of CF. In the case of a newborn identified by neonatal screening, and of course with the parents’ permission, the siblings and blood relatives of child bearing age should be offered checking for mutations as part of cascade screening and the parents and siblings informed of the results. Unfortunately this still occurs in less than half the instances when a newborn is identified as having CF by screening.

2016 Vears DF; Delany C; Massie J; Gillam L Why Do Parents Want to Know their Child’s Carrier Status? A Qualitative Study.  J Genet Counsel 2016 May 19. [PubMed]
To address this question, semi-structured interviews were conducted with parents of 32 children with cystic fibrosis, haemophilia, and Duchenne muscular dystrophy who wanted to know the carrier status of their other children. Data was analysed using inductive content analysis. Parents expressed a range of reasons for desiring their child’s carrier status, which fell into two broad categories: 1) benefit for the parents and 2) perceived benefit to the child. Parents discussed the desire for certainty and peace of mind derived from having knowledge of their child’s status.

The most commonly expressed reason for wanting to know their child’s carrier status was in order to communicate the information to their child to provide them with the ability to make informed reproductive decisions.These reasons suggest parents are seeking their children’s carrier information both as a coping strategy and to communicate carrier information as part of their role as a parent. This has important implications for genetic counseling practice, especially as international guidelines generally recommend against carrier testing in children.

– As cascade screening of CF relatives still has only some 50% take up in the most recent reports, it is sensible to identify carriers at an early stage. In conditions such as CF identification of carrier couples can avoid the birth of a CF infant by use of preimplantation genetic diagnosis. The study seems to indicate that parents would not agree with the present “international guidelines”.

2016 Yao R, Goetzinger KR. Genetic Carrier Screening in the Twenty-first Century. Cli Lab Med. 2016 Jun;36(2):277-88. doi: 10.1016/j.cll.2016.01.003. Epub 2016 Mar 5. [PubMed]
Historically, carrier screening for a small number of autosomal recessive disorders has been offered to targeted populations based on ethnicity and family history. These chosen disorders are associated with severe morbidity or mortality, have a well-established carrier frequency in the targeted population, and have an acceptably high detection rate to make screening efficient. With advancing genetic technology, expanded panels rapidly are being designed and offered to the panethnic general population. This article reviews current recommendations for ethnicity-specific carrier screening for common disorders as well as the limitations and counselling complexities associated with expanded panels.

Selected Key Points in the article relevant to CF — Carrier screening for cystic fibrosis should be offered to all patients in the preconception or prenatal period regardless of ethnicity

– American College of Medical Genetics currently supports a carrier screening panel for 9 disorders for persons of Ashkenazi Jewish descent; however, expanded panels are available

Pre and post test genetic counselling, including residual risk estimation should be made available to all couples undergoing carrier screening.

In 1997, the National Institutes of Health (NIH) held a consensus conference to address the complex issues associated with CF carrier screening in a panethnic population. This conference was followed, in 1998, by an additional NIH conference directed at the implementation of this committee’s recommendations. Based on these recommendations, CF carrier screening was to be offered to (1) adults with a positive family history of CF, (2) partners of known CF carriers, (3) couples currently planning a pregnancy, and (4) couples seeking prenatal care (NIH Consensus Development Conference Statement on genetic testing for cystic fibrosis Arch Int Med 1999; 159:1529-39).

In 2001, recommendations were issued from another steering committee composed of representatives from the American College of Medical Genetics (ACMG), the American College of Obstetricians and Gynecologists (ACOG), and the National Human Genome Research Institute. This group recommended narrowing the screening population to non-Jewish white people and Ashkenazi Jews, although testing was still made available to other ethnic groups with informed consent and recognition of limitations of screening (Grody WW et al, Genet Med 2001;3:149-54).

In addition, in 2005, ACOG revised its recommendations to state that it is reasonable to offer CF carrier screening to all patients, with the caveat that screening is most efficacious in the non-Hispanic white and Ashkenazi Jewish populations. This recommendation is based on the fact that it is becoming increasingly difficult to assign an individual to any particular ethnic group. Patients electing carrier screening for CF should undergo both pretest and post test counselling, with particular attention paid to ethnic background, detection rate, and residual risk estimate.- This is a very useful review article of the present position.

The UK seems to be slow to recommend prenatal and antenatal screening. The UK National Screening Committee did not recommend this screening in 2006 and failed to review their decision in 2010 as promised. However, the matter was to be reviewed in 2017.

As far back as 1999 a UK Health Technology Assessment recommended antenatal CF screening should be offered routinely to women and their partners in all maternity units. Also it was observed that pre-conceptional screening would provide more reproductive options and should be made available in the family planning clinic or GP setting for couples without a family history who request the test because a pregnancy is planned. Also screening should be made available in assisted reproduction units for those having ICSI and for sperm donors (Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J. Screening for cystic fibrosis. Health Technol Assess 1999; 3(8))1999. [PubMed] Full article available). This recommendation was rejected on the grounds of expense by the National UK Screening Committee as was the HTA’s recommendation for neonatal CF screening although neonatal screening was eventually approved by the Government in 2001 and eventually implemented countrywide by 2007.

2016 Zlotogora J, Grotto I, Kaliner E, Gamzu R. The Israeli national population program of genetic carrier screening for reproductive purposes. Genet Med. 2016 Feb;18(2):203-6. doi: 10.1038/gim.2015.55. Epub 2015 Apr 16. [PubMed]
The Israeli population genetic screening program for reproductive purposes, launched in January 2013, includes all known, nationally frequent severe diseases (carrier frequency 1:60 and/or disease frequency 1 in 15,000 live births). The carrier-screening program is free of charge and offers testing for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy for nearly the entire population, according to disease frequency among the different groups within the population.

The authors report the results of the first year of the program.Data on the tests performed over a 12-month period were collected from laboratories nationwide. More than 62,000 individuals were examined. The carrier frequency was within the expected range for most of the diseases. The few exceptions included lower carrier rates for cystic fibrosis among Muslim Arabs (1:236) and Druze (1:1,021) and Niemann-Pick type A among Muslim Arabs in a delineated region of Israel (1:229)

The national population genetic carrier screening is aimed toward providing couples with knowledge of the existing options for the prevention of serious genetic conditions when it is relevant for them. The authors suggest that it is still too early to determine whether this aim has been achieved.

2017 Bombard Y, Miller FA, Barg CJ, Patton SJ, Carroll JC, Chakraborty P, Potter BK, Tam K, Taylor L, Kerr E, Davies C, Milburn J, Ratjen F, Guttmann A, Hayeems RZ. A secondary benefit: the reproductive impact of carrier results from newborn screening for cystic fibrosis. Genet Med. 2017 Apr;19(4):403-411. doi: 10.1038/gim.2016.125. Epub 2016 Sep 8.[Pubmed]

Newborn screening (NBS) for cystic fibrosis (CF) can identify carriers, which is considered a benefit that enables reproductive planning. The authors examined the reproductive impact of carrier result disclosure of NBS for CF.  They surveyed mothers of carrier infants after NBS (Time 1) and 1 year later (Time 2) to ascertain intended and reported communication of their infants’ carrier results to relatives, carrier testing for themselves/other children, and reproductive decisions. A sub-sample of mothers was also interviewed at Time 1 and Time 2.

The response rate was 54%. A little more than half (55%) of mothers underwent carrier testing at Time 1; another 40% of those who intended to undergo testing at Time 1 underwent testing at Time 2. Carrier result communication to relatives was high (92%), but a majority of participants did not expect the results to influence family planning (65%). All interviewed mothers valued learning their infants’ carrier results. Some underwent carrier testing and then shared results with family. Others did not use the results or used them in unintended ways.

The authors concluded that, although mothers valued learning carrier results from NBS, they reported moderate uptake of carrier testing and limited influence on family planning. The study highlights the secondary nature of the benefit of disclosing carrier results of NBS.

~ These findings reflect the disappointingly low interest the public have in pursuing carrier testing among their partners and relatives even when they learn a member of the family is a CF carrier.

Dr. Yvaonne Bombard (figure) is a genomics health services researcher and Scientist at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital. She is an Assistant Professor at the University of Toronto in the Institute of Health Policy Management and Evaluation.

2017 Archibald AD, Smith MJ, Burgess T, Scarff KL, Elliott J, Hunt CE, Barns-Jenkins C, Holt C, Sandoval K, Siva Kumar V, Ward L, Allen EC, Collis SV, Cowie S, Francis D, Delatycki MB, Yiu EM, Massie RJ, Pertile MD, du Sart D, Bruno D, Amor DJ  Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. Genet Med. 2017 Oct 26. doi: 10.1038/gim.2017.134. [Epub ahead of print]   [Pubmed] A report, from Victoria Australia, of experience of offering simultaneous genetic carrier screening for cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA). Carrier screening is offered through general practice, obstetrics, fertility, and genetics settings before or in early pregnancy. Carriers are offered genetic counselling with prenatal/preimplantation genetic diagnosis available to those at increased risk.

Screening of 12,000 individuals revealed 610 carriers (5.08%; 1 in 20): 342 CF, 35 FXS, 241 SMA (8 carriers of 2 conditions), approximately 88% of whom had no family history. At least 94% of CF and SMA carriers’ partners were tested. Fifty couples (0.42%; 1 in 240) were at increased risk of having a child with one of the conditions (14 CF, 35 FXS, and 1 SMA) with 32 pregnant at the time of testing. Of these, 26 opted for prenatal diagnosis revealing 7 pregnancies affected (4 CF, 2 FXS, 1 SMA). The combined affected pregnancy rate is comparable to the population risk for Down syndrome, emphasizing the need to routinely offer carrier screening. The availability of appropriate genetic counselling support and a collaborative approach between laboratory teams, genetics services, health professionals offering screening, and support organizations is essential.

Dr Alison Archibald is associate Genetic Counsellor at the Victorian Genetics Services.

Braverman G, Shapiro ZE, Bernstein JA.  Ethical Issues in Contemporary Clinical Genetics. Mayo Clin Proc Innov Qual Outcomes. 2018 May 8;2(2):81-90. doi: 10.1016/j.mayocpiqo.2018.03.005. eCollection  2018 Jun.   30225437 ? [Pubmed]    Free PMC Article
This article provides an overview of the salient ethical concerns pertaining to clinical genetics. The subject is approached with an emphasis on clinical practice, but consideration is also given to research. The review is organized around the temporal and informational sequence of issues commonly arising during the course of pretesting, testing, and post-testing phases of patient care. Drawing from medical, legal, and historical perspectives, this review covers the following topics: (1) informed consent, (2) return of results, and (3) privacy and confidentiality, and intends to equip readers with an appropriate foundation to apply ethical principles to genetic testing paradigms with an understanding of the contextual landscape against which these situations occur.

Dr G Braverman at the Department of Internal Medicine, New York Presbyterian Hospital – Columbia University Medical Center, New York

Chokoshvili D, Vears D, Borry P.Expanded carrier screening for monogenic disorders: where are we now?   Prenat Diagn. 2018 Jan;38(1):59-66. doi: 10.1002/pd.5109. Epub 2017 Jul 27  [Pubmed]

To identify relevant expanded carrier screening (ECS) providers, we employed a multi-step approach, which included online searching, review of the recent literature, and consultations with researchers familiar with the current landscape of ECS.   As of January 2017, there were 16 providers of ECS tests: 13 commercial companies, 2 medical hospitals, and 1 academic diagnostic laboratory. The authors noted drastic differences in the characteristics of ECS tests, with the number of conditions ranging from 41 to 1792. Only three conditions (cystic fibrosis, maple syrup urine disease 1b, and Niemann-Pick disease) were screened for by all providers. Where the same disease gene was included by multiple providers, substantial differences existed in the mutations screened and/or variant interpretation/reporting strategie

The authors suggested that, given the importance of carrier screening results in reproductive decision-making, the observed heterogeneity across ECS panels is concerning. Efforts should be made to ensure that clear and concrete criteria are in place to guide the development of ECS panels.

– This study is from University of Leuven, Belgium

Dr. Davit Chokoshvili (figure)  is a doctoral researcher at the Centre for Biomedical Ethics and Law. Leuven

Di Pietro ML, Teleman AA, Gonzalez-Melado FJ, Zace D, Di Raimo FR, Lucidi V, Refolo P.     Implementing carrier screening for cystic fibrosis outside the clinic: ethical analysis in the light of the personalist view. 2018 Mar-Apr;169(2):e71-e76. doi: 10.7417/T.2018.2057.  Free full text [Pubmed]

Cystic Fibrosis (CF) is an autosomal recessive genetic disease. Two models for screening CF are normally used: newborn screening and population-based CF carrier screening. In turn, there are three main models of population-based CF carrier screening: prenatal carrier screening, preconception carrier screening, and carrier screening outside clinical settings.  Purpose of this study was to evaluate, in the light of the personalist view, the use of carrier screenings for CF outside the clinic, i.e. in non-clinical settings, such as school and workplaces.

An analysis has been carried out according to the “Personalist approach” (also called “Triangular model”), an ethical method for performing ethical analysis within HTA process. It includes factual, anthropological and ethical data in a ”triangular” normative reflection process.

Implementing carrier screening for cystic fibrosis outside the clinical settings allows acquisition of knowledge for informing reproductive choices, that can be considered as valuable; benefit-risk ratio seems to be not much favourable; autonomous and responsible decisions can be taken only under certain conditions; economic advantage is difficult to determine; therefore, from a personalist view, implementing carrier screenings outside the clinic seems not to be ethically justified.

So these authors conclude in accordance with the “personalist perspective”, public health programs providing carrier screenings outside the clinic should not be implemented.

Corresponding author is Dr. Pietro Refolo. Institute of Bioethics, Catholic University of the Sacred Heart, Milano Italy.

– This article is difficult for anyone not already familiar with “personalism” (including the present writer!). Described as a theory or system based on subjective ideas or applications. The theory that probabilities do not have objective meaning but are expressions of a personal perspective on the occurrence of events.  A system of thought which maintains the primacy of the human or divine person on the basis that reality has meaning only through the conscious mind.

Certainly the authors emphasise some of the real problems such as the screened person’s lack of understanding of the meaning of the results. Yet one cannot agree with their conclusions. This writer (JML) believes the CF is now largely a preventable condition and both carrier screening and also in preimplantation genetic diagnosis should be more widely publicised and be available to all.

Gorrie A, Archibald AD, Ioannou L, Curnow L, McClaren B. Exploring approaches to facilitate family communication of genetic risk information after cystic fibrosis population carrier screening.   J Community Genet. 2018 Jan;9(1):71-80. doi: 10.1007/s12687-017-0337-1. Epub 2017 Oct 2.  Free PMC Article [Pubmed]
Population carrier screening for cystic fibrosis (CF) enables individuals with no known family history of the condition to ascertain their risk of having a child with CF. When an individual is identified as a carrier of CF, a life-shortening condition, they are encouraged to inform their relatives who are at increased risk of being a carrier. Research suggests that the uptake of CF carrier testing amongst relatives of carriers or people with CF is low. This study aimed to explore approaches to facilitate the process of family communication of genetic information after an individual is identified as a carrier of CF through population screening. Five key informants were interviewed to inform the development of a telephone survey which was administered to 21 individuals identified as carriers of CF through population carrier screening at Victorian Clinical Genetics Services.

–   This study suggests that providing carriers with additional information and follow-up support would be appreciated by carriers and could result in more accurate information being disseminated more widely within families, which could lead to more at-risk relatives accessing testing. Suggested strategies to enhance current practice include mailing a fact sheet to carriers and a follow-up telephone call provided by a genetic counsellor to carriers to offer further support in communicating this information to their relatives.

Gregg AR. Expanded Carrier Screening. Obstet Gynecol Clin North Am. 2018 Mar;45(1):103-112. doi: 10.1016/j.ogc.2017.10.005.     [Pubmed]

Prenatal carrier screening has expanded to include a larger number of genes and variants offered to all couples considering or with an on going pregnancy. Panethnic screening for cystic fibrosis and spinal muscular atrophy and screening for a limited number of conditions based on ethnicity are recommended by the American College of Obstetricians and Gynecologists. Residual risk calculations have become an obsolete part of post-test counselling when expanded carrier screening (ECS) is selected. The Perception of Uncertainties in Genome Sequencing scale offers a useful understanding of the pre-test and post-test counselling concerns that should be considered as part of ECS implementation

Dr. Anthony Gregg is in the Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

Harper JC,. Preimplantation genetic screening. J Med Screen 12018 Mar; 24(1):1-5.  [Pubmed]  

Preimplantation genetic diagnosis was first successfully performed in 1989 as an alternative to prenatal diagnosis for couples at risk of transmitting a genetic or chromosomal abnormality, such as cystic fibrosis, to their child. From embryos generated in vitro, biopsied cells are genetically tested. From the mid-1990s, this technology has been employed as an embryo selection tool for patients undergoing in vitro fertilisation, screening as many chromosomes as possible, in the hope that selecting chromosomally normal embryos will lead to higher implantation and decreased miscarriage rates. This procedure, preimplantation genetic screening, was initially performed using fluorescent in situ hybridisation, but 11 randomised   controlled trials of screening using this technique showed no improvement in in vitro fertilisation delivery rates. Progress in genetic testing has led to the introduction of array comparative genomic hybridisation, quantitative polymerase chain reaction, and next generation sequencing for preimplantation genetic screening, and three small randomised controlled trials of preimplantation genetic screening using these new techniques indicate a modest benefit. Other trials are still in progress but, regardless of their results, preimplantation genetic screening is now being offered globally. In the near future, it is likely that sequencing will be used to screen the full genetic code of the embryoA study.

Joyce Harper is Professor of Human Genetics and Embryology at the  Institute for Women’s Health, University College London, London, UK.

Holtkamp KCA, Henneman L, Gille JJP, Meijers-Heijboer H, Cornel MC Lakeman P.  Direct-to-consumer carrier screening for cystic fibrosis via a hospital website: a 6-year evaluation.  J Community Genet. 2018 Sep 18. doi: 10.1007/s12687-018-0388-y. [Epub ahead of print] [Pubmed]

A Dutch university hospital started offering cystic fibrosis (CF) carrier screening directly to consumers (DTC) through their website in 2010. A 6-year process evaluation was conducted to evaluate the offer. Screening was implemented as intended. However, uptake was lower than expected. Forty-four tests have been requested, partly by couples with a positive family history for CF, which was not the intended target group. Users were generally positive about the screening offer, citing accessibility, ease of testing, anonymity, and perceived shortcomings of regular healthcare as reasons for requesting screening.

DTC CF carrier screening via a university hospital website is feasible, but is seldom used. Considering technological advances, continuation of this specific offer is questionable.

Kim Holtkamp is a Researcher in Community Genetics Department of Clinical Genetics, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Mosconi P, Colombo C, Roberto A, Candiani G, Greco MT, Satolli R, Castellani C. Deciding on cystic fibrosis carrier screening: three citizens’ juries and an online survey.  Eur J Public Health. 2018 Mar 19. doi: 10.1093/eurpub/cky032. [Epub ahead of print]   [Pubmed]

A citizens’ jury is one way to ask citizens to deliberate on controversial topics in the interests of a society. The aims of this project were to gather opinions about CF carrier screening through citizens’ jury deliberations and to match them with the findings of a large online consultation survey open to the general population, people with CF and families and health professionals.

Three citizens’ juries and an online survey were asked: ‘Should the Health Service organize screening of the population with the aim of identifying healthy people who may have children with CF?’ The jurors had no medical background and no personal or family CF history. The survey was open to people with CF, families, and healthcare professionals.

Jurors and survey respondents were in favour of CF carrier screening, mainly considering the severity of CF, the value of informed reproductive choices and the equality of the screening. All the citizens’ juries felt positively about the health service actively offer CF carrier screening to provide women and couples of reproductive age equal access and standardized information on the pros and cons.

Considering the favourable attitude towards CF screening, the feasibility of CF screening, in terms of best setting, target age and healthcare professionals providing it, should be tested in a clinical trial.

O’Connor K, Jukes T, Goobie S, DiRaimo J, Moran G, Potter BK, Chakraborty P, Rupar CA, Gannavarapu S, Prasad C.Psychosocial impact on mothers receiving expanded newborn screening results.
Eur J Hum Genet. 2018 Apr;26(4):477-484. doi: 10.1038/s41431-017-0069-z. Epub 2018 Jan 29. [Pubmed]
Expanded newborn screening (NBS) for genetic disorders has improved diagnosis of numerous treatable diseases, positively impacting children’s health outcomes. However, research about the psychological impact of expanded NBS on families, especially mothers, has been mixed. Our study examined associations between maternal experiences of expanded NBS and subsequent psychosocial functioning and parenting stress in mothers whose infants received either true negative (TN), true positive (TP) or false positive (FP) results after a 4- to 6-month period. The Parenting Stress Index and the Depression, Anxiety and Stress Scale were used to assess symptoms of anxiety, stress and depression in 3 sets of mothers, whose infants received TN (n = 31), TP (n = 8) or FP (n = 18) results. Multivariate analyses of variance (MANOVA) results revealed no significant differences among these three groups of mothers regarding overall anxiety, stress and depression. However, FP mothers experienced lower levels of stress related to their own health compared to TN group. Two potential trends were also identified; results suggested TN mothers might experience higher levels of isolation than mothers in the TP group and that FP mothers might report higher stress levels in relation to spousal relationships compared to the TN group. FP mothers seemed to report similar or better levels of psychosocial functioning than TN mothers.

The authors consider their findings are encouraging with respect to impacts of NBS on maternal well-being. We also identify key areas for improvement (parental education) and research (isolation and spousal relationships).

From Western University London, Ontario.

Albu CC, Stancu IG, Grigore LG, Albu DF, Albu ŞD, Pătraşcu A, Gogănău AM.mpact of genetic testing and family health history of cystic fibrosis in the early prenatal diagnosis and prevention of a new case of genetic disorder.  Rom J Morphol Embryol. 2019;60(2):667-671. Free full text [Pubmed]
The authors state the aim of the present case report is to highlight the importance of genetic testing in the early prenatal diagnosis and prevention of a new case of CF. Cystic fibrosis (CF) is a multi-system autosomal recessive disorder, results of mutations in the CF transmembrane conductance regulator (CFTR) gene, located on the long arm of chromosome 7. We present a special family couple with particular medical history of CF, who comes to our Clinic for genetic tests and a prenatal genetic counseling, to prevent the birth of a new affected CF child. Genetic analysis showed that the first affected child, a daughter, is compound heterozygous for two clinically significant recessive mutations: c.1521_1523delCTT; p.Phe508del, inherited from her mother, who carries the same CFTR mutation, and c.1853_1863delTTTTGCATGAA; p.IIe618Argfs 2, inherited from her father, who is heterozygous, healthy carrier, for the same CFTR mutation. In our case report, early prenatal genetic testing, pre- and post-test genetic counseling was crucial in the management of the present pregnancy, to prevent the birth of a new affected CF child.

 Dr Cristina Crenguta Albu is a lecturer in the Department of Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; crenguta.albu@yahoo.com.

Boëlle PY, Debray D, Guillot L, Clement A, Corvol H; French CF Modifier Gene Study Investigators. Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients.Hepatology. 2019 Apr;69(4):1648-1656. doi: 10.1002/hep.30148. Epub 2018 Dec 28. [Pubmed]

Cystic fibrosis (CF)-related liver disease (CFLD) is a common symptom in patients with CF. However, its prevalence, risk factors, and evolution are unclear. We analyzed a large database of patients with CF to investigate the incidence of CFLD, its related risk factors, and the use and effect of ursodeoxycholic acid (UDCA) treatment. We retrospectively analyzed 3,328 CF patients with pancreatic insufficiency born after 1985 and recruited into the French CF Modifier Gene Study since 2004. We determined liver status, age at CFLD and severe CFLD onset, sex, CFTR genotype, history of meconium ileus, treatment with UDCA, and respiratory and nutritional status.

The incidence of CFLD increased by approximately 1% every year, reaching 32.2% by age 25. The incidence of severe CFLD increased only after the age of 5, reaching 10% by age 30. Risk factors for CFLD and severe CFLD were male sex, CFTR F508del homozygosity, and history of meconium ileus. Increasingly precocious initiation of UDCA treatment did not change the incidence of severe CFLD. Finally, patients with severe CFLD had worse lung function and nutritional status than other CF patients.

The authors concluded CFLD occurs not only during childhood but also later in the lifetime of patients with CF; male sex, CFTR F508del homozygosity, and history of meconium ileus are independent risk factors for CFLD development; earlier use of UDCA over the last 20 years has not changed the incidence of severe CFLD, leading to questions about the use of this treatment in young children given its possible adverse effects.

– Another large study in CFLD from France with similar findings to those of Toledano et al 2019 using the UK CF Patient Registry data. In contrast to this French study, the UK data identified a positive association with survival and the use of URSO.

Chandler NJ, Ahlfors H, Drury S, Mellis R, Hill M, McKay FJ, Collinson C, Hayward J, Jenkins L, Chitty LS. Noninvasive Prenatal Diagnosis for Cystic Fibrosis: Implementation, Uptake, Outcome, and Implications.Clin Chem. 2019 Sep 24. pii: clinchem.2019.305011. doi: 10.1373/clinchem.2019.305011. [Epub ahead of print] [Pubmed] Non-invasive prenatal diagnosis (NIPD) for monogenic disorders has a high uptake by families. Since 2013, our accredited public health service laboratory has offered NIPD for monogenic disorders, predominantly for de novo or paternally dominantly inherited mutations. Here we describe the extension of this service to include definitive NIPD for a recessive condition, cystic fibrosis (CF). Definitive NIPD for CF was developed using next-generation sequencing. Validation was performed on 13 cases from 10 families before implementation. All cases referred for CF NIPD were reviewed to determine turnaround times, genotyping results, and pregnancy outcomes.

Of 38 referrals, 36 received a result with a mean turnaround of 5.75 days (range, 3-11 days). Nine cases were initially inconclusive, with 3 reported unaffected because the low-risk paternal allele was inherited and 4 cases in which the high-risk paternal allele was inherited, receiving conclusive results following repeat testing. One case was inconclusive owing to a paternal recombination around the mutation site, and one case was uninformative because of no heterozygosity. Before 2016, 3 invasive referrals for CF were received annually compared with 38 for NIPD in the 24 months since offering a definitive NIPD service.

The authors concluded timely and accurate NIPD for definitive prenatal diagnosis of CF is possible in a public health service laboratory. The method detects recombinations, and the service is well-received as evidenced by the significant increase in referrals. The bioinformatic approach is gene agnostic and will be used to expand the range of conditions tested for.

Hayward J, Chitty LS. Beyond screening for chromosomal abnormalities: Advances in non-invasive diagnosis of single gene disorders and fetal exome sequencing. Semin Fetal Neonatal Med. 2018 Apr;23(2):94-101. doi: 10.1016/j.siny.2017.12.002. Epub 2018 Jan 2. [Pubmed] Emerging genomic technologies, largely based around next generation sequencing (NGS), are offering new promise for safer prenatal genetic diagnosis. These innovative approaches will improve screening for fetal aneuploidy, allow definitive non-invasive prenatal diagnosis (NIPD) of single gene disorders at an early gestational stage without the need for invasive testing, and improve our ability to detect monogenic disorders as the aetiology of fetal abnormalities. This presents clinicians and scientists with novel challenges as well as opportunities. In addition, the transformation of prenatal genetic testing arising from the introduction of whole genome, exome and targeted NGS produces unprecedented volumes of data requiring complex analysis and interpretation. Now translating these technologies to the clinic has become the goal of clinical genomics, transforming modern healthcare and personalized medicine. The achievement of this goal requires the most progressive technological tools for rapid high-throughput data generation at an affordable cost. Furthermore, as larger proportions of patients with genetic disease are identified we must be ready to offer appropriate genetic counselling to families and potential parents. In addition, the identification of novel treatment targets will continue to be explored, which is likely to introduce ethical considerations, particularly if genome editing techniques are included in these targeted treatments and transferred into mainstream personalized healthcare.

Here the authors review the impact of NGS technology to analyse cell-free DNA (cfDNA) in maternal plasma to deliver NIPD for monogenic disorders and allow more comprehensive investigation of the abnormal fetus through the use of exome sequencing.

Professor Lynn Chitty is Professor of Genetics & Fetal Medicine. From North East Thames Regional Genetics Laboratory, Great Ormond Street NHS Foundation Trust, London, UK.

Course CW, Hanks R. Newborn screening for cystic fibrosis: Is there benefit for everyone? Paediatr Respir Rev. 2019 Aug;31:3-5. doi: 10.1016/j.prrv.2019.02.003. Epub 2019 Feb 28. [Pubmed]
Newborn screening for cystic fibrosis (CF) has become a widely accepted and endorsed public health strategy in economically developed countries, although there is little consensus on optimal screening methods and gene panels. Increasing understanding of CFTR genetics and consequent unpredictability of phenotypic and clinical outcomes lead to diagnostic uncertainty, and emergence of Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CF-SPID). Many of these children are clinically well or have a mild phenotype yet may still experience the psychosocial impact of a CF diagnosis. This questions the role of newborn screening and how best to manage those it identifies with CF-SPID.

From Department of Paediatric Respiratory Medicine and Cystic Fibrosis, Children’s Hospital for Wales, Cardiff, United Kingdom. 

–  It is difficult to see how the occurrence of CF-SPID “questions the role of newborn screening” the introduction of which has been one of the major advances in CF care over the past 40 years.

Kessels SJM, Carter D, Ellery B, Newton S, Merlin TL. Prenatal genetic testing for cystic fibrosis: a systematic review of clinical effectiveness and an ethics review. Genet Med. 2019 Aug 30. doi: 10.1038/s41436-019-0641-8. [Epub ahead of print] [Pubmed]

To determine effectiveness of prenatal genetic testing the authors conducted a systematic literature review whose protocol outlined search strategies across eight databases, study inclusion criteria, and pre-specified literature screening, data extraction, and synthesis processes. We conducted a scoping search on ethical considerations.The genetic test showed good diagnostic performance. A change in clinical management was observed: termination of pregnancy (TOP) occurred in most cases where two pathogenic variants were identified in a fetus of carrier parents (158/167; 94.6%). The TOP rate was lower in pregnancies where CF was diagnosed after fetal echogenic bowel detection (~65%). TOP and caring for a child with CF were both associated with poor short-term parental psychological outcomes. Ethical analyses indicated that informed decisions should have been the main endpoint, rather than CF-affected births prevented.

The authors concluded CF testing leads to fewer CF-affected births. It is difficult to assess whether this means the test is valuable, since patients may not value TOP primarily in terms of maternal or fetal health outcomes, psychological or otherwise. The value of testing should arguably be measured in terms of improving patient autonomy rather than health.

– A very clear article on a difficult subject. Recommended.

Sharon Kessels is Senior Research Officer, Adelaide Health Technology Assessment (AHTA), School of Public Health, The University of Adelaide, Adelaide, SA, Australia.

Dr Drew Carter Research Fellow, Ethics, Adelaide Health Technology Assessment (AHTA), School of Public Health, The University of Adelaide, Adelaide, SA, Australia. Described as a moral philosopher and health policy researcher who works mostly at the interface of ethics and health economics.

Pierre-Yves Boelle is Professor at the Pierre and Marie Curie University Paris

Sugunaraj JP, Brosius HM, Murray MF, Manickam K, Stamm JA, Carey DJ, Mirshahi UL.Predictive value of genomic screening: cross-sectional study of cystic fibrosis in 50,788 electronic health records. NPJ Genom Med. 2019 Sep 4;4:21. doi: 10.1038/s41525-019-0095-6. eCollection 2019. free PMC article [Pubmed]

Doubts have been raised about the value of DNA-based screening for low-prevalence monogenic conditions following reports of testing this approach using available electronic health record (EHR) as the sole phenotyping source. We hypothesized that a better model for EHR-focused examination of DNA-based screening is Cystic Fibrosis (CF) since the diagnosis is proactively sought within the healthcare system. We reviewed CFTR variants in 50,778 exomes. In 24 cases with bi-allelic pathogenic CFTR variants, there were 21 true-positives. We considered three cases “potential” false-positives due to limitations in available EHR phenotype data. This genomic screening exhibited a positive predictive value of 87.5%, negative predictive value of 99.9%, sensitivity of 95.5%, and a specificity of 99.9%. Despite EHR-based phenotyping limitations in three cases, the presence or absence of pathogenic CFTR variants has strong predictive value for CF diagnosis when EHR data is used as the sole phenotyping source. Accurate ascertainment of the predictive value of DNA-based screening requires condition-specific phenotyping beyond available EHR data.

Dr Jaya Sugunaraj is an Associate at Geisinger Danville Pemmsylvania

Braverman G, Shapiro ZE, Bernstein JA.  Ethical Issues in Contemporary Clinical Genetics. Mayo Clin Proc Innov Qual Outcomes. 2018 May 8;2(2):81-90. doi: 10.1016/j.mayocpiqo.2018.03.005. eCollection  2018 Jun.  30225437  [Pubmed]       This article provides an overview of the salient ethical concerns pertaining to clinical genetics. The subject is approached with an emphasis on clinical practice, but consideration is also given to research. The review is organized around the temporal and informational sequence of issues commonly arising during the course of pretesting, testing, and post-testing phases of patient care. Drawing from medical, legal, and historical perspectives, this review covers the following topics: (1) informed consent, (2) return of results, and (3) privacy and confidentiality, and intends to equip readers with an appropriate foundation to apply ethical principles to genetic testing paradigms with an understanding of the contextual landscape against which these situations occur.

Dr G Braverman at the Department of Internal Medicine, New York Presbyterian Hospital – Columbia University Medical Center, New York

Chokoshvili D, Vears D, Borry P. Expanded carrier screening for monogenic disorders: where are we now? Prenat Diagn. 2018 Jan;38(1):59-66. doi: 10.1002/pd.5109. Epub 2017 Jul 27  [Pubmed]

The authors suggested that, given the importance of carrier screening results in reproductive decision-making, the observed heterogeneity across ECS panels is concerning. Efforts should be made to ensure that clear and concrete criteria are in place to guide the development of ECS panels.

– This study is from University of Leuven, Belgium

Dr. Davit Chokoshvili (figure)  is a doctoral researcher at the Centre for Biomedical Ethics and Law. Leuve

Gregg AR. Expanded Carrier Screening. Obstet Gynecol Clin North Am. 2018 Mar;45(1):103-112. doi: 10.1016/j.ogc.2017.10.005.     [Pubmed]

Prenatal carrier screening has expanded to include a larger number of genes and variants offered to all couples considering or with an on going pregnancy. Panethnic screening for cystic fibrosis and spinal muscular atrophy and screening for a limited number of conditions based on ethnicity are recommended by the American College of Obstetricians and Gynecologists. Residual risk calculations have become an obsolete part of post-test counselling when expanded carrier screening (ECS) is selected. The Perception of Uncertainties in Genome Sequencing scale offers a useful understanding of the pre-test and post-test counselling concerns that should be considered as part of ECS implementation.

Dr. Anthony Gregg is in the Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

Anthony R Gregg, Janice G Edwards^.  Prenatal genetic carrier screening in the genomic age.  Semin Perinatol. 2018 Aug;42(5):303-306.doi: 10.1053/j.semperi.2018.07.019.Epub 2018 Jul 26. [Pubmed]

The Society for Maternal-Fetal Medicine, American College of Obstetricians and Gynecologists (ACOG), and American College of Medical Genetics and Genomics (ACMG) held a workshop entitled “Prenatal Genetic Testing” on January 25, 2017 to address several questions arising from the increasing implementation of preconception and prenatal expanded carrier screening (ECS). ECS allows for identification of a greater number of genetic sequencing changes (not all of which cause disease) and simultaneous testing for an increased number of genetic conditions without limitation to specific ethnic groups.
The workshop participants reached consensus on the following: ethnicity based testing cannot be completely abandoned in favor of panethnic ECS; the specific approach to screening should be a patient’s choice and not driven solely by provider preference; organizations should work to develop a framework for vetting conditions that should be    reported on ECS panels; compared with prenatal screening, preconception screening is ideal and, at this time, due to the costs and the need for timeliness associated with prenatal screening, post-test counselling and testing, that when ECS is offered it should be presented as a preconception option; preconception and prenatal panels should be identical across the spectrum of patients, including those undergoing assisted reproduction; adult-onset conditions should not be included on ECS panels; partners should be offered next-generation sequencing to identify rare variants when the first partner screened is determined to be a carrier; re-screening in subsequent pregnancies is not indicated, despite the potential for expansion of carrier screening conditions and variants; and more education about ECS for providers and patients is necessary to implement prenatal carrier screening in a responsible way.

Anthony Gregg, Chief Obstetrics and Gynecology, Maternal Fetal Medicine, Baylor University Medical Center, 3500 Gaston Ave., Dallas, and President of the American College of Medical Genetics and Genomics.

Janice G Edwards Director of the Genetic Counseling Program, School of Medicine, University of South Carolina, Columbia,

Chandler NJ, Ahlfors H, Drury S, Mellis R, Hill M, McKay FJ, Collinson C, Hayward J, Jenkins L, Chitty LS. Noninvasive Prenatal Diagnosis for Cystic Fibrosis: Implementation, Uptake, Outcome, and Implications.Clin Chem. 2019 Sep 24. pii: clinchem.2019.305011. doi: 10.1373/clinchem.2019.305011. [Epub ahead of print] [Pubmed] Non-invasive prenatal diagnosis (NIPD) for monogenic disorders has a high uptake by families. Since 2013, our accredited public health service laboratory has offered NIPD for monogenic disorders, predominantly for de novo or paternally dominantly inherited mutations. Here we describe the extension of this service to include definitive NIPD for a recessive condition, cystic fibrosis (CF). Definitive NIPD for CF was developed using next-generation sequencing. Validation was performed on 13 cases from 10 families before implementation. All cases referred for CF NIPD were reviewed to determine turnaround times, genotyping results, and pregnancy outcomes.

Of 38 referrals, 36 received a result with a mean turnaround of 5.75 days (range, 3-11 days). Nine cases were initially inconclusive, with 3 reported unaffected because the low-risk paternal allele was inherited and 4 cases in which the high-risk paternal allele was inherited, receiving conclusive results following repeat testing. One case was inconclusive owing to a paternal recombination around the mutation site, and one case was uninformative because of no heterozygosity. Before 2016, 3 invasive referrals for CF were received annually compared with 38 for NIPD in the 24 months since offering a definitive NIPD service.

The authors concluded timely and accurate NIPD for definitive prenatal diagnosis of CF is possible in a public health service laboratory. The method detects recombinations, and the service is well-received as evidenced by the significant increase in referrals. The bioinformatic approach is gene agnostic and will be used to expand the range of conditions tested for.

From the NE Thames Regional Genetics Laboratories, Great Ormond Street Hospital, London, UK.

Hayward J, Chitty LS. Beyond screening for chromosomal abnormalities: Advances in non-invasive diagnosis of single gene disorders and fetal exome sequencing. Semin Fetal Neonatal Med. 2018 Apr;23(2):94-101. doi: 10.1016/j.siny.2017.12.002. Epub 2018 Jan 2. [Pubmed] Emerging genomic technologies, largely based around next generation sequencing (NGS), are offering new promise for safer prenatal genetic diagnosis. These innovative approaches will improve screening for fetal aneuploidy, allow definitive non-invasive prenatal diagnosis (NIPD) of single gene disorders at an early gestational stage without the need for invasive testing, and improve our ability to detect monogenic disorders as the aetiology of fetal abnormalities. This presents clinicians and scientists with novel challenges as well as opportunities. In addition, the transformation of prenatal genetic testing arising from the introduction of whole genome, exome and targeted NGS produces unprecedented volumes of data requiring complex analysis and interpretation. Now translating these technologies to the clinic has become the goal of clinical genomics, transforming modern healthcare and personalized medicine. The achievement of this goal requires the most progressive technological tools for rapid high-throughput data generation at an affordable cost. Furthermore, as larger proportions of patients with genetic disease are identified we must be ready to offer appropriate genetic counselling to families and potential parents. In addition, the identification of novel treatment targets will continue to be explored, which is likely to introduce ethical considerations, particularly if genome editing techniques are included in these targeted treatments and transferred into mainstream personalized healthcare.

Here the authors review the impact of NGS technology to analyse cell-free DNA (cfDNA) in maternal plasma to deliver NIPD for monogenic disorders and allow more comprehensive investigation of the abnormal fetus through the use of exome sequencing.

Professor Lynn Chitty is Professor of Genetics & Fetal Medicine. From North East Thames Regional Genetics Laboratory, Great Ormond Street NHS Foundation Trust, London, UK.

Stephanie C M Nijmeijer, Thirsa Conijn, Phillis Lakeman, Lidewij Henneman, Frits A Wijburg, Lotte Haverman^. Attitudes of the general population towards preconception expanded carrier screening for autosomal recessive disorders including inborn errors of metabolism. Mol Genet Metab . 2019 Jan;126(1):14-22.doi: 10.1016/j.ymgme.2018.12.004. Epub 2018 Dec 10.[Pubmed]

Background: A substantial number of severely debilitating and often ultimately fatal inborn errors of metabolism (IEMs) still lack an effective disease-modifying treatment. Informing couples before a pregnancy about an increased risk of having a child with an inherited disorder is now feasible by preconception expanded carrier screening (ECS). While knowledge about carrier status enhances reproductive autonomy, it may also result in ethical dilemmas. The purpose of this study was to assess the attitudes of the general Dutch population towards preconception ECS and to investigate which factors influence these attitudes.
Methods: Data collection was carried out in collaboration with a market research agency. In total, 1188 Dutch individuals of reproductive age (18-45 years) were invited by email to complete an online ECS questionnaire in 2016. Prior to the start of the questionnaire, a written explanation of the concepts of autosomal recessive (AR) inheritance, carrier status and ECS was presented.
Results: The questionnaire was completed by 781 individuals (65.7%), of whom 31% indicated they would take an ECS test themselves. In addition, 55% agreed that ECS should be offered to all prospective parents. The most frequently selected argument in favor of ECS (47.2%) was that participants want to spare a child from a life with a severe hereditary disorder. The reason most often mentioned not to participate in ECS (48%) was that participants reported not having a hereditary disorder in the family. The majority preferred receiving individual test results above a couple-based disclosure method in which participants receive the carrier status results only when they are a carrier couple of the same disorder. Participants with religious beliefs were less likely to participate in ECS, whereas participants who were considering a (future) pregnancy were more likely to participate.
Conclusion: Our study demonstrates an overall positive attitude among participants of reproductive age in the general Dutch population towards preconception ECS. A striking misconception is that many of the participants believe that ECS is of interest only for those with a positive family history of one of the hereditary disorders. This finding emphasizes the importance of providing understandable, balanced information and education to the general public regarding the concepts of inheritance when presenting the option of carrier screening. Our results provide valuable insights that can be used in the debate about the responsible implementation of preconception expanded carrier screening or autosomal recessive disorders, including inborn errors of metabolism .

Dr Stephanie C M Nijmeijer Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children’s Hospital and Amsterdam Lysosome Center “Sphinx”, Amsterdam, Netherlands.

Delatycki MB, Alkuraya F, Archibald A, Castellani C, Cornel M, Grody WW, Henneman L, Ioannides AS, Kirk E, Laing N, Lucassen A, Massie J, Schuurmans J, Thong MK, van Langen I, Zlotogora J.  International perspectives on the implementation of reproductive carrier screening. Prenat Diagn. 2019 Nov 27. doi: 10.1002/pd.5611. [Epub ahead of print] [Pubmed]

Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay-Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X-linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples  before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry-based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. 

– This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.

Professor Martin B Delatycki is Group Leader Genetics, Victorian Clinical Genetics Services, Parkville, Victoria, Australia.

Bener A, Al-Mulla M, Clarke A.    Premarital Screening and Genetic Counseling Program: Studies from an Endogamous Population.     Int J Appl Basic Med Res. 2019 Jan-Mar;9(1):20-26. doi: 10.4103/ijabmr.IJABMR_42_18. [Pubmed]
Studies in Arab countries have shown a significant lack of knowledge of Premarital Screening and Genetic Counseling (PMSGC) Program. PMSGC can identify and modify, through prevention and management, some behavioral, medical, and other health risk factors known to impact pregnancy outcomes.
The aim of this study was to explore the knowledge, attitudes, and practice of Qatari’s toward the premarital screening program and shedding more light on a complex matter.
The current study revealed that knowledge and attitude regarding PMSGC program were low in population. Motivation, enforcement, and implementation of program at the school and university educational campaigns are vital. Improved counseling and adding new topics for counseling on genetic, chronic, and mental illness; building healthy families; and reproduction and fertility are considered to be top priorities in community

 Dr A Bener from the Department of Biostatistics and Medical Informatics, Cerrahpasa Faculty of Medicineistanbul, Istanbul University, İstanbul, Turkey. Other authors are  from Manchester, Qatar and Cardiff

 Hernandez-Nieto C, Alkon-Meadows T, Lee J, Cacchione T, Iyune-Cojab E, Garza-Galvan M, Luna-Rojas M, Copperman AB, Sandler B.  Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population.  Prenat Diagn. 2020 Jan 31. doi: 10.1002/pd.5656. [Epub ahead of print]  [Pubmed]

Genetic carrier screening has the potential to identify couples at risk of having a child affected with an autosomal recessive or X-linked disorder. However, the current prevalence of carrier status for these conditions in developing countries is not well defined. This study assesses the prevalence of carrier status of selected genetic conditions utilizing an expanded, pan-ethnic genetic carrier screening panel (ECS) in a large population of Mexican patients.
A retrospective chart review of all patients tested with a single ECS panel at an international infertility centre from 2012-2018 were included, the prevalence of positive carrier status in a Mexican population was evaluated.
805 individuals were analysed with ECS testing for 283 genetic conditions. 352 carriers (43.7%) were identified with 503 pathogenic variants in 145 different genes. Seventeen of the 391 participating couples (4.34%) were identified as being at-risk couples. The most prevalent alleles found were associated with alpha-thalassemia, cystic fibrosis, GJB2 non-syndromic hearing loss, biotinidase deficiency, and familial Mediterranean fever.

Based on the prevalence and severity of Mendelian disorders, the authors recommend that couples, who wish to conceive regardless of their ethnicity background, explore carrier screening and genetic counselling prior to reproductive medical treatment.

Dr Carlos Alberto Hernández Nieto is Reproductive Endocrinologist at Reproductive Medicine Associates of New York, New York, United States and Mexico, Mexico City, Mexico

Bieth E, Nectoux J, Girardet A, Gruchy N, Mittre H, Laurans M, Guenet D, Brouard J, Gerard M. Genetic counseling for cystic fibrosis: A basic model with new challenges. Arch Pediatr. 2020 Feb;27 Suppl 1:eS30-eS34. doi: 10.1016/S0929-693X(20)30048-8. [Pubmed]
While the goals of genetic counseling for cystic fibrosis – delivering relevant information on the risk of recurrence and nondirectional support of couples at risk in their reproductive choices – have not changed fundamentally, the practice has evolved considerably in the last decade, growing more complex to face new challenges but also proving more effective. Many factors have contributed to this evolution: technical progress in the exploration of the genome (new generation sequencing) and in reproductive medicine, but also societal developments promoting access to genetic information and the professionalization of genetic counselors in France. The prospect of expanded pre-conception screening of at-risk couples makes genetic counselors major actors not only in medical care centers, but also in modern society by contributing to genetic education among citizens.

Dr Eric Bieth is at Génétique Médicale, CHU Toulouse, France.

 Marco L Leung, Sallie McAdoo , Deborah Watson , Kallyn Stumm , Margaret Harr , Xiang Wang , Christine H Chung, Fernanda Mafra, Addie I Nesbitt, Hakon Hakonarson, Avni Santani  A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening.   J Mol Diagn 2021 Jan;23(1):91-102. doi: 10.1016/j.jmoldx.2020.10.009.   

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature
As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these data

Marco L Leung at the Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania;

Molly R Payne, Anne-Bine Skytte, Joyce C Harper The use of expanded carrier screening of gamete donors.  Hum Reprod. 2021 Apr 11;deab067.doi: 10.1093/humrep/deab067. Online ahead of print. [Pubmed]

Study question: What are the sperm and egg donor rejection rates after expanded carrier screening (ECS)?
Summary answer: Using an ECS panel looking at 46/47 genes, 17.6% of donors were rejected.
What is known already: The use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available.
Study design, size, duration: A review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS.
Participants/materials, setting, methods: Data on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data.
Main results and the role of chance: A total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155).
Limitations, reasons for caution: Panel information was found on company websites and may not have been accurate.
Wider implications of the findings: This study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients

Lauren A Thomas, Sharon Lewis, John Massie, Edwin P Kirk, Alison D Archibald, Kristine Barlow-Stewart, Felicity K Boardman, Jane Halliday, Belinda McClaren, Martin B Delatycki   Which types of conditions should be included in reproductive genetic carrier screening? Views of parents of children with a genetic condition. Eur J Med Genet 2020 Dec;63(12):104075.doi: 10.1016/j.ejmg.2020.104075.Epub 2020 Sep 30 [Pubmed]
Reproductive genetic carrier screening identifies couples with an increased chance of having children with autosomal and X-linked recessive conditions. Initially only offered for single conditions to people with a high priori risk, carrier screening is becoming increasingly offered to individuals/couples in the general population for a wider range of genetic conditions. Despite advances in genomic testing technology and greater availability of carrier screening panels, there is no consensus around which types of conditions to include in carrier screening panels.

This study sought to identify which types of conditions parents of children with a genetic condition believe should be included in carrier screening. Participants (n = 150) were recruited through Royal Children’s Hospital (RCH) Melbourne outpatient clinics, the Genetic Support Network of Victoria (GSNV) and a databank of children with hearing loss (VicCHILD).

This study found that the majority of participants support offering carrier screening for: neuromuscular conditions (n = 128/134, 95.5%), early fatal neurodegenerative conditions (n = 130/141, 92.2%), chronic multi-system disorders (n = 124/135, 91.9%), conditions which cause intellectual disability (n = 128/139, 92.1%) and treatable metabolic conditions (n = 120/138, 87.0%). Views towards the inclusion of non-syndromic hearing loss (n = 88/135, 65.2%) and preventable adult-onset conditions (n = 75/135, 55.6%) were more mixed. Most participants indicated that they would use reproductive options to avoid having a child with the more clinically severe conditions, but most would not do so for clinically milder conditions. A recurring association was observed between participants’ views towards carrier screening and their lived experience of having a child with a genetic condition.

Dr Lauren A Thomas at the Department of Paediatrics, University of Melbourne, Australia and Victorian Clinical Genetics Services, Australia.

Molly Payne is Genetic Technologist at Royal Devon and Exeter NHS Trust   Exeter, England,

A Capalbo, M Fabiani, S Caroselli, M Poli, L Girardi, C Patassini, F Favero, D Cimadomo, A Vaiarelli, C Simon, L F Rienzi, F M Ubaldi Clinical validity and utility of preconception expanded carrier screening for the management of reproductive genetic risk in IVF and general population. Hum Reprod 2021 May 22;deab087.doi: 10.1093/humrep/deab087. Online ahead of print.[Pubmed]

Study question: What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents?
Summary answer: The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population.
What is known already: About 2-4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds    the potential to significantly improve couple’s genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring.
Study design, size, duration: A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples.
Participants/materials, setting, methods: A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making.
Main results and the role of chance: A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby.
Limitations, reasons for caution: The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene-disease associations

Dr A Capalbo is Laboratory Manager  at Igenomix Italy.

Anthony R Gregg, Mahmoud Aarabi, Susan Klugman, Natalia T Leach, Michael T Bashford, Tamar Goldwaser, Emily Chen, Teresa N Sparks, Honey V Reddi, Aleksandar Rajkovic, Jeffrey S Dungan, ACMG Professional Practice and Guidelines Committee.Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG).  Genet Med 2021 Jul 20.doi: 10.1038/s41436-021-01203-z. Online ahead of print. [Pubmed]

Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay-Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase “expanded carrier screening” is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency.
This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.

Dr Anthony R Gregg is at the Department of Obstetrics and Gynecology, Prisma Health, Columbia, SC, USA.

Wider implications of the findings: These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF.

Chadia Mekki, Abdel Aissat, Véronique Mirlesse, Sophie Mayer Lacrosniere, Elsa Eche, Annick Le Floch, Sandra Whalen, Cecile Prud’Homme, Christelle Remus, Benoit Funalot, Vanina Castaigne, Pascale Fanen, Alix de Becdelièvre.  Prenatal Ultrasound Suspicion of Cystic Fibrosis in a Multiethnic Population: Is Extensive CFTRGenotyping Needed?  Genes (Basel) 2021 Apr 29;12(5):670.doi: 10.3390/genes12050670.   Free PMC article. [Pubmed]

In families without a Cystic Fibrosis (CF) history, fetal ultrasound bowel abnormalities can unexpectedly reveal the disease. Isolated or in association, the signs can be fetal bowel hyperechogenicity, intestinal loop dilatation and non-visualization of fetal gallbladder. In these cases, search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the recommended diagnostic practices, with a search for frequent mutations according to ethnicity, and, in case of the triad of signs, with an exhaustive study of the gene. However, the molecular diagnosis remains a challenge in populations without well-known frequent pathogenic variants. We present a multiethnic cohort of 108 pregnancies with fetal bowel abnormalities in which the parents benefited from an exhaustive study of the CFTR gene. We describe the new homozygous p.Cys1410* mutation in a fetus of African origin. We did not observe the most frequent p.Phe508del mutation in our cohort but evidenced variants undetected by our frequent mutations kit. Thanks to the progress of sequencing techniques and despite the difficulties of interpretation occasionally encountered, we discuss the need to carry out a comprehensive CFTR study in all patients in case of fetal bowel abnormalities.

Dr Chadia Mekki is in the Departement de Genetique, DMU Biologie-Pathologie, GH Mondor-Chenevier, AP-HP, F-94010 Creteil, France.

Shan Riku, Herman Hedriana, Jacqueline A Carozza, Jennifer Hoskovec^.  Reflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower cost.  J Med Econ Jan-Dec 2022;25(1):403-411. doi: 10.1080/13696998.2022.2053384. Free article [Pubmed]

Objective: To evaluate the clinical benefits and achievable cost savings associated with the adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care.
Method: A decision-analytic model was developed to compare carrier screen with reflex sgNIPT (maternal carrier status and fetal risk reported together) as first-line carrier screening to the traditional carrier screening workflow (positive maternal carrier screen followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and healthcare costs associated with the two screening methods. These results were used to simulate appropriate pricing for reflex sgNIPT.
Results: Reflex sgNIPT carrier screening-detected 108 of 110 affected pregnancies per 100,000 births (98.5% sensitivity), whereas traditional carrier screening-detected 46 of 110 affected pregnancies (41.5% sensitivity). The cost to identify one affected pregnancy was reduced by 62% in the reflex sgNIPT scenario compared to the traditional scenario. Adding together the testing cost savings and the savings from earlier clinical intervention made possible by reflex sgNIPT, the total cost savings was $37.6 million per 100,000 pregnancies. Based on these cost savings, we simulated appropriate reflex sgNIPT pricing range: if the cost to identify one affected pregnancy is the unit cost, carrier screening with reflex sgNIPT can be priced up to $1,859 per test (or $7,233 if sgNIPT is billed separately); if the cost per 100,000 pregnancies is the unit cost, carrier screening with sgNIPT can be priced up to $1,070 per test (or $2,336 if sgNIPT is billed separately).

Conclusion: Using the carrier screen with reflex sgNIPT as first-line screening improves the detection of affected fetuses by 2.4-fold and can save costs for the healthcare system. A real-life experience will be needed to assess the clinical utility and exact cost savings of carrier screen with reflex sgNIPT.

 Shan Riku is SVP of Product at BillionToOne, Inc., Menlo Park, CA, USA.

Maeve K Hopkins, Lorraine Dugoff, Jeffrey A Kuller.  Guidelines for Cystic Fibrosis Carrier Screening in the Prenatal/Preconception Period.   Review Obstet Gynecol Surv. 2022 Oct;77(10):606-610. doi: 10.1097/OGX.0000000000001062. pubmed.ncbi.nlm.nih.gov/36242530/

Importance: Cystic fibrosis (CF) is one of the most common autosomal recessive disorders. Carrier screening for CF should be offered to all women considering becoming pregnant or who are pregnant. Understanding the available screening tests, their limitations, and the benefits of screening is of paramount importance to the obstetrician-gynecologist.
Objectives: The objective is to review the current guidelines for CF carrier screening including the options for carrier screening, the potential complexities associated with carrier screening for CF, and indications for referral to certified genetic counselors or maternal-fetal medicine specialists.
Evidence acquisition: A MEDLINE search of “cystic fibrosis,” “cystic fibrosis carrier screening pregnancy,” and “inheritance of cystic fibrosis” in the review was performed.
Results: The evidence cited in this review includes 2 medical society committee opinions and 15 additional peer-reviewed journal articles that were original research or expert opinion summaries.

Conclusions and relevance: The American College of Obstetricians and Gynecologists recommends that obstetricians offer CF carrier screening to all pregnant women or women considering becoming pregnant. Based on recent guidelines from ACMG, additional expanded carrier screening can be recommended to patients in the future, with additional CF variants and other autosomal or X-linked recessive conditions. It is important for the prenatal care provider to understand the guidelines for carrier screening as well as the potential complexities associated with carrier screening due to the multiple pathogenic variants in the CFTR gene that may be associated with varying phenotypes. With the options for CF carrier screening, screening performance in different populations, a basic understanding of the disease and interpretation of carrier screening results is of paramount importance to the prenatal care provider.

Maeve K Hopkins is Clinical Professor, Division of Maternal-Fetal Medicine, Women’s Health Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, OH.

Neeta L Vora.  Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions.  Genet Med. 2022 Dec 1;S1098-3600(22)01002-4.  doi: 10.1016/j.gim.2022.10.014. Online ahead of print.pubmed.ncbi.nlm.nih.gov/36454238/

 Purpose: The purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene non-invasive prenatal screening (sgNIPS), which does not require paternal carrier screening
Methods: An unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies.
Results: Overall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected.

Conclusion: Although traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (∼10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management.

Jennifer Hoskovec is Director of medical Affaires at BillionToOne, Inc, Menlo Park, CA.

Line Dahl Jeppesen , Dorte Launholt Lildballe, Lotte Hatt , Jakob Hedegaard  , Ripudaman Singh , Christian Liebst Frisk Toft , Palle Schelde  , Anders Sune Pedersen , Michael Knudsen, Ida Vogel. Noninvasive prenatal screening for cystic fibrosis using circulating trophoblasts: Detection of the 50 most common disease-causing variants.   Prenat Diagn. 2022 Nov 29.  doi: 10.1002/pd.6276.  Online ahead of print. pubmed.ncbi.nlm.nih.gov/36447355/

Objectives: Cystic fibrosis (CF) is one of the most common severe autosomal recessive disorders. Prenatal or preconception CF screening is offered in some countries. A maternal blood sample in early pregnancy can provide circulating trophoblasts and offers a DNA source for genetic analysis of both the mother and the fetus. This study aimed to develop a cell-based noninvasive prenatal test (NIPT) to screen for the 50 most common CF variants.
Methods: Blood samples were collected from 30 pregnancies undergoing invasive diagnostics and circulating trophoblasts were harvested in 27. CF testing was conducted using two different methods: By fragment length analysis and by our newly developed NGS-based CF analysis RESULTS: In all 27 cases, cell-based NIPT provided a result using both methods in agreement with the invasive test result.

Conclusion: This study shows that cell-based NIPT for CF screening provides a reliable result without the need for partner- and proband samples.

Line Dahl Jeppesen is a PhD student at Vejle, Denmark.and Center for Fetal Diagnostics, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.