The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

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 Eventually both methods were superseded by superior DNA based methods.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amniotic fluid supernatant had a rational physiological basis and had stood the test of time but eventually it was superseded by superior DNA-based methods.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.

 

David Brock 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 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 2012 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) 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 2014. 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.

 

 

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.

 

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.

 

 

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. We 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.

 

Alan Handyside

Professor Alan Handyside,(figure) one of the pioneers of PGD, suggesting the need for a national IVF-PGD programme. (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).

 

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.

 

 

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. We discuss some of the ethical issues raised by the policies and individual choices that are the subject of this study. In particular, (1) we discuss the ethical issues raised by the acquisition of genetic information through antenatal carrier testing; (2) we 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) we consider whether by choosing to avoid natural procreation carrier couples can harm current or future individuals affected by cystic fibrosis; (4) we discuss whether programs that make carrier testing available can be considered eugenic programs.

 


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.

 

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.


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.
 
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 programme.
 
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 a summary of the main messages 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.
 
 

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 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.

Anne Girardet

 
Anne Girardet received her PhD in Molecular Genetics from the University Montpellier, France, in 1998. She now performs PGD in this centre where she has set up several single gene disorder protocols for PGD purposes.

 

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 many 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 net
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 NIPD 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.
 
 
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. doi: 10.1007/s10897-015-9833-9. Epub 2015 May 1. [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 Jul 29. doi: 10.1038/ejhg.2015.160. [Epub ahead of print]  [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. (See Topics-> Diagnosis-> Antenatal/Prenatal).   It is  unfortunate that the recent impressive and 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 pregnancy.

 

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]  25880436[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.

 


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 invitro 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.

 

 
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 Jul 29. doi: 10.1038/ejhg.2015.160. [Epub ahead of print]     [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. (See Topics-> Diagnosis-> Antenatal/Prenatal).   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 pregnancy.

 

 

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. doi: 10.1007/s10897-015-9833-9. Epub 2015 May 1. [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 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 net IN TOPICS
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 NIPD 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.