RESUMEN
BACKGROUND: Primary ovarian insufficiency (POI) affects around 2-4% of women before the age of 40. Genetic factors play an important role in POI. The GDF9 gene has been identified as a significant genetic contributor of POI. However, the pathogenicity and penetrance of GDF9 variants remain uncertain. METHODS: A next-generation sequencing approach was employed to investigate the entire coding region of the GDF9 gene in a cohort of 1281 patients with POI or diminished ovarian reserve (DOR). The frequency of each identified GDF9 variant was then compared with that of the general population, taking into account the ethnicity of each individual. RESULTS: By screening the entire coding region of the GDF9 gene, we identified 19 different variants, including 1 pathogenic frameshift variant. In total, 36 patients with POI/DOR (2.8%) carried at least one GDF9 variant. With regard to missense variants, no significant overrepresentation of the most common variants was observed in our POI/DOR cohort in comparison to the general or specific ethnic subgroups. Only one homozygous subject had a frameshift loss of function variant. CONCLUSION: This epidemiological study suggests that the vast majority of heterozygous missense variants could be considered as variants of uncertain significance and the homozygous loss-of-function variant could be considered as a pathogenic variant. The identification of a novel case of a homozygous POI patient with a heterozygous mother carrying the same variant with normal ovarian function strongly suggests that GDF9 syndrome is an autosomal recessive disorder.