Introduction to the genetics of female infertility: The vital TUBB8 fertility gene

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

These relatively newly discovered variants are found in many different fertility genes that have been shown to affect fertilisation and different stages of pregnancy. These variants can be roughly categorised into different groups that significantly affect either only women’s fertility or only men’s fertility and a small number of genes that are vital for both men’s and women’s fertility.

Infertile couples diagnosed with unexplained infertility by an assisted conception clinic usually undergo either In Vitro Fertilisation (IVF) or Intra Cytoplasmic Sperm Injection (ICSI). A successful pregnancy using these techniques requires the following successful steps to be completed:

1) Healthy maturation of egg or sperm.
2) Successful fertilisation of the egg by a single sperm.
3) Early embryonic development.
4) Successful Implantation of an early embryo.
5) Successful development of the embryo into a healthy baby.

Failure at any of these stages will lead to either male or female infertility, recurrent failure of IVF cycles or recurrent pregnancy loss.

Recently, several studies have reported that variants in a single gene known as TUBB8 can result in failure at any one of the first three steps shown above.

To date, at least 102 different unrelated women of different ethnicities have been shown to be infertile due to many different mutations in the TUBB8 gene, which consistently caused fertilisation failure following either conventional IVF or ICSI. The vast majority of such patients possess both one normal and one variant copy of the TUBB8 gene. These variants are either inherited from the patient’s father or are due to a rare 1 in a million new mutation, occurring during the development of either the parent’s ovum or sperm DNA. In a small number of cases, the patients possess two mutated copies.

The TUBB8 gene makes one of several essential so called “structural proteins” known as Tubulins, which have been shown to be essential for the fertilised egg to divide and make an embryo. Any changes in the Tubulin 8 protein caused by a single or double variant in the TUBB8 gene will stop the egg dividing after fertilisation, and the embryo will fail to develop, thus consistently causing female infertility. Therefore the only option for such patients shown to be suffering from TUBB8 infertility is egg donation.

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