Scientists at deCODE Genetics and collaborators have identified a sequence variant in the CCDC201 gene that, when inherited homozygously from both parents, is associated with early onset of menopause by an average of nine years.
deCODE Genetics, an Amgen subsidiary, and collaborators in Iceland, Denmark, the UK and Norway published findings today in Nature Genetics identifying a rare genotype with significant implications for women's health.
Age at menopause significantly impacts fertility and disease risk. The study focused on the recessive model, or individuals with two copies of the sequence variant, called homozygotes, which are less studied than the additive model, which mainly relies on an individual having one copy of the sequence variant, especially when this is rare. By analyzing data from over 174,000 women from Iceland, Denmark, the UK, and Norway, the researchers discovered a stop-gain mutation that leads to an arginine to termination change at position 162 of the CCDC201 gene, which has a dramatic impact on AOM.
The CCDC201 gene was first identified as a human protein-coding gene in 2022 and has since been shown to be highly expressed in egg cells, and this study demonstrates that its complete loss of function has significant implications for female reproductive health.
Women with two copies of this variant are called homozygotes and reach menopause an average of nine years earlier than non-carriers. This homozygous genotype is found in approximately 1 in 10,000 women of Northern European descent and causes primary ovarian insufficiency in almost half of carriers, defined as menopause before age 40. As a result, women with this genotype have fewer children, and very rarely have children after age 30.
This finding highlights the importance of considering different genetic models in understanding diseases such as primary ovarian failure.
This study highlights the potential benefits of genetic counselling for women with this particular genotype: early diagnosis allows for informed reproductive choices and management of symptoms associated with early menopause.
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Journal References:
Oddsson, A., et al. (2024). Homozygosity for a stop-gain mutation in CCDC201 causes primary ovarian failure. Nature Genetics. doi.org/10.1038/s41588-024-01885-6.
