The genetic revolution that is now diagnosing couples with “unexplained infertility”

Explaining the unexplainable: The genetic revolution that is now diagnosing couples with “unexplained infertility”.

1 in 7 couples worldwide are diagnosed with fertility problems. Moreover, as many as 1 in 3 couples, who then attend an assisted conception clinic, are given the highly unsatisfactory diagnosis of unexplained infertility. This is a heartbreaking for such couples, who have usually undergone numerous time consuming gynaecological and andrological tests only to have no concrete conclusions.

However, new research now suggests that in at least half of such unexplained infertility cases, there is a known genetic explanation. With approximately half of the underlying genetic variant or variants being carried by the man, while the other half will be carried by the woman.

These relatively newly discovered variants/mutations found in several different fertility genes have been shown to affect fertilisation as well as different stages of pregnancy and can be roughly categorised into six different groups that significantly affect either only women’s (4 groups) or only men’s fertility (2 groups).

Women’s categories:

1) Oocyte maturation defects caused by single variants/mutations, such as the TUBB8 gene which can lead to consistent failure of IVF or ICSI (Intracytoplasmic sperm injection).

2) Preimplantation embryonic lethality, such as in the case of the PAD16 gene, which consistently causes a lack of embryo development after successful fertilisation.

3) Recurrent pregnancy loss, such as variants in the SCYP3 gene leading to the loss of a pregnancy.

4) Hydatidiform mole in the case of the NALP7 gene, which leads to an abnormal pregnancy caused due to abnormally formed placental tissue. Here if a foetus forms it cannot survive and is usually miscarried in early pregnancy.

With Oocyte maturation defects, a woman would either use ICSI or egg donation, depending on the specific gene involved to become pregnant, while with Preimplantation embryonic lethality, Recurrent pregnancy loss and Hydatidiform a woman would usually always require egg donation to achieve pregnancy.

Men’s categories:

1) Reduced sperm motility and failure of sperm to penetrate the egg is caused by mutations in the CATSPERE gene. This is not always picked up by clinics and will usually require ICSI to achieve pregnancy.

2) Oocyte activation failure caused by the PLCZ1 gene again is not usually picked up by clinics will usually require enhanced ICSI (ICSI+) to achieve pregnancy.

Most of the reported gene variants/mutations affect either men or women, but not both. However, there are a few reported genes whose variants/mutations can affect both men and women, such as the SCYP3 gene. In women, this can cause recurrent pregnancy loss while in men it can cause nonobstructive azoospermia, where the men completely lack sperm in their semen.

In conclusion, the large number of variants/mutations in fertility genes, are now being reported at an exponentially increasing rate due to the recent advances in DNA sequencing technology. Happily, it is therefore now feasible to routinely screen for such variants/mutations in couples diagnosed with unexplained infertility. This will undoubtedly lead to firstly help explain the previously unexplainable to such couples and secondly and more importantly will help them immediately choose their fastest route to pregnancy.

My future blogs will go into more depth on each particular unexplained infertility gene category and possible routes to fertilisation to overcome the variants/mutations in these genes.

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