to reduce the couple’s reproductive risk of conceiving an affected child from 50% to <1%. PGT is performed on amplified DNA extracted from a trophectoderm biopsy obtained from a day 5 or 6 blastocyst‐stage embryo using whole genome amplification (WGA) and preimplantation genetic haplotyping (PGH) after establishing phase using blood samples obtained from the male partner’s parents [5].
Alternatively, the couple could opt for PESA and ICSI followed by prenatal testing by chorionic villus sampling (CVS) or amniocentesis with termination of an affected pregnancy. If the couple in Case History 1 object to termination of pregnancy due to social, cultural or religious reasons, they could opt for either PGT or use sperm donated from a cystic fibrosis–negative donor.
Case history 2
This couple are fertile and don’t necessarily require assisted conception technology to conceive. Their reproductive options are either ICSI using ejaculated sperm followed by PGT on trophectoderm biopsy obtained from a day 5/6 blastocyst‐stage embryo or prenatal screening after natural conception and termination of an affected pregnancy. Using donor sperm from a cystic fibrosis–negative donor if they object to termination of pregnancy would be another option.
The expected chance of success of PGT per cycle is 40–50% when the female partner’s age is below 35 as in both case histories. Cost‐effectiveness of this treatment modality has been established [6].
Ethical considerations
There are two main ethical issues involved in both case histories. The first relates to the morality of terminating a pregnancy affected with cystic fibrosis when the disease expression is variable and could range from very mild to severe, and advances in medical management of the disease have progressed to the stage where living a relatively fulfilling life until the fourth decade of life is commonplace. The second issue is the notion of replacing cystic fibrosis carrier embryos after PGT. In view of the complete lack of symptoms in cystic fibrosis carriers, discarding a cystic fibrosis carrier embryo at the time of PGT may be considered by some tantamount to eugenics. These are challenging situations and difficult decisions, and affected couples should be fully counseled and appropriately supported.
The future
Increased PGT test accuracy and reduced cost is likely to improve its uptake among at‐risk couples [7]. In addition, better understanding of the genetic basis for cystic fibrosis will shed new light on the underlying pathophysiology of the disease and help develop now therapeutic approaches such as CFTR replacement and gene therapy [8]. It will also direct future research to help eliminate or reduce the substantial burden of the disease. Currently, PGT, early postnatal diagnosis and aggressive therapy remain the mainstay of modern prevention and treatment of cystic fibrosis in the infertile couple.
Key points
Challenge: Cystic fibrosis in a couple of reproductive age and its relation to their fertility.
Background:
Cystic fibrosis is the most common life‐threatening autosomal recessive condition in Caucasians, with an estimated carrier rate of 1 in 25.
Approximately, 98% of men affected with cystic fibrosis are azoospermic, due to congenital bilateral absence of the vas deferens (CBAVD).
The most common mutation is the delta‐F508 mutation, present in 75% of cases.
Reproductive risks will depend on accurate genetic diagnosis in both partners.
Management:
The expertise of fertility specialists and a genetics center with advanced molecular diagnostic facilities are required for optimum management.
Diagnosis should involve extended genetic testing of both partners to appreciate the extent of genetic risks to the future child.
Treatment options include surgical sperm retrieval followed by ICSI with or without PGT, prenatal screening and termination of an affected pregnancy or using donor sperm obtained from a cystic fibrosis–negative donor.
Success rate of PGT is acceptable and the treatment is considered cost‐effective.
Appropriate genetic and fertility counseling is paramount throughout the whole process.
Answers to questions patients ask
1 Q1 What causes cystic fibrosis?A1. Cystic fibrosis is caused by sequence variation in the CFTR (cystic fibrosis transmembrane regulator) gene, located on chromosome 7.
2 Q2 How common is cystic fibrosis?A2. Cystic fibrosis is one of the most common genetic conditions in European population, and 1 in every 2,500 babies born in the UK has cystic fibrosis. The carrier rate in Western Europe is about 1 in 25.
3 Q3 What are the medical effects of cystic fibrosis?A3. Cystic fibrosis results in the production of an abnormally thickened mucous secretions in various body organs, including lungs, pancreas, bowel and biliary ducts. This causes obstruction and chronic inflammation and progressive organ failure.
4 Q4 How can cystic fibrosis cause infertility?A4. Cystic fibrosis in the male is associated with bilateral absence of the vas deferens which is the tube that conveys the sperm from the testicles to the urethra. In the female, cystic fibrosis causes infertility via cervical canal or fallopian tubal obstruction due to the production of viscid and tenacious cervical and tubal secretions.
5 Q5 What is the first step in initiating PGT treatment?A5. Cystic fibrosis is one of the most common indications for PGT, and almost 10% of all PGT cycles performed worldwide are to avoid a pregnancy affected with cystic fibrosis. It is important that couples considering PGT receive adequate genetic counseling before starting the treatment process to understand the testing and the available reproductive options.
References
1 1 Welsh MJ, Denning GM, Ostedgaard LS, Anderson MP. Dysfunction of CFTR bearing the delta F508 mutation. J Cell Sci Suppl. 1993; 17:235–9.
2 2 van der Ven K, Messer L, van der Ven H, Jeyendran RS, Ober C. Cystic fibrosis mutation screening in healthy men with reduced sperm quality. Hum Reprod. 1996; 11: 513–7.
3 3 Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, Maher TA, White MB, Milunsky A. Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. JAMA. 1992; 267:1794–7.
4 4 Grangeia A, Sá R, Carvalho F, Martin J, Girodon E, Silva J, Ferráz L, Barros A, Sousa M. Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. Genet Med. 2007; 9:163–72.
5 5 Girardet A, Viart V, Plaza S, Daina G, De Rycke M, Des Georges M, et al. The improvement of the Best Practice Guidelines for Preimplantation Genetic Diagnosis of cystic fibrosis: towards an international consensus. Eur J Hum Genet. 2016; 24(4): 469–78.
6 6 Davis L, Champion S, Fair S, Baker V, Garber A. A cost‐benefit analysis of preimplantation genetic diagnosis for carrier couples of cystic fibrosis. Fertil Steril. 2010; 93:1793–1804.
7 7 Chamayou S, Sicali M, Lombardo D, Alecci C, Ragolia C, Maglia E, et al. Universal strategy for preimplantation testing for cystic fibrosis based on next generation sequencing. J Assist Reprod Genet. 2019; 37(1):213–212. DOI: 10.1007/s10815‐019‐01635‐2.
8 8 Guggino WB, Cebotaru L. Adeno‐associated Virus (AAV) genetherapy for cystic fibrosis: current barriers and recent developments. Expert Opin Bio Ther. 2017; 17:1265–73.
7 The patient on medication
Pedro Meloand Arri Coomarasamy