Assisted Reproduction Techniques. Группа авторов

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genetic counseling is an integral part of the two couples’ management to explain the genetic test results and emphasize the reproductive risks and wider family implications.

      Case history 1

      If the female partner was found to be a carrier of a cystic fibrosis mutation after extended mutation screening, this couple will have a 50% risk of conceiving a child affected with cystic fibrosis, although the range of phenotypic expression could be wide and vary from very mild to severe clinical manifestations. In addition, 50% of this couple’s children will be carriers of a cystic fibrosis mutation. If the female partner is tested negative for cystic fibrosis mutation, the risk of conceiving a child affected with cystic fibrosis drops to approximately 1 in 1,000.

      Case history 2

      If extended cystic fibrosis testing in this couple fails to reveal a second mutation in either partner, their risk of conceiving a second child affected with cystic fibrosis is 25%, and 50% of their children will be carriers of the delta‐F508 mutation. Statistically, a quarter of this couple’s children are likely to be healthy noncarriers.

      Treatment options

      The treatment options available for the couple in Case History 1 differ considerably from those available for the couple in Case History 2.

      Case history 1

      If the female partner was found to be a carrier of a cystic fibrosis mutation, in conjunction with ICSI and where expertise and facilities allow, the couple would ideally be offered preimplantation genetic testing (PGT) to ensure only embryos unaffected by cystic fibrosis are transferred in utero. PGT has the ability 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.

      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

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