Chromosomal and genetic causes of primary ovarian insufficiency in the Utah population.

Gradient of genetic burden: chromosomal abnormalities and recessive inheritance in primary amenorrhoea, heterozygous rare variants (DNA damage repair) and polygenic risk in secondary amenorrhoea

This population-based study in Utah combines chart review and genome sequencing to describe the causes of primary ovarian insufficiency (POI). Of 899 women, 289 (32.1%) had Turner syndrome; among the other 610, an established clinical aetiology was found in 8.1%, including FMR1 premutations (2.6%), chromosomal abnormalities (1.5%) and adrenal autoimmunity (1.8%). Among 68 women without an identified cause who underwent genome sequencing, a likely causal genetic diagnosis was made in 17.6% (12/68), with recessive variants enriched in primary amenorrhoea and heterozygous or multiple rare variants in DNA damage repair pathways in secondary amenorrhoea. Mean polygenic score for age at natural menopause did not differ from controls, but a low score compounded risk in a subset of rare-variant carriers.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The baseline figures are useful for the work-up: Turner syndrome in a third of POI cases, FMR1 premutation in 2.6% of the others, and a contributory genome in nearly one in five cases when the standard work-up is negative. The sequenced sample (68) remains small, and the polygenic score, relevant only in a subgroup, has no demonstrated individual clinical utility. By contrast, the primary versus secondary amenorrhoea distinction as a pointer to the expected genetic model is a practical guide.

Analysis by Dr Thibaut Benquey