From Dominant Assumptions to Recessive Trait: Rethinking BMP15 in Ovarian Dysfunction

Abstract

Approximately 1% of women experience premature ovarian insufficiency (POI) before the age of 40. Genetic factors play a significant role in the development of POI. The BMP15 gene is one of the first genes involved in POI. However, the pathogenicity and the penetrance of BMP15 variants still remain unclear. A cohort of 500 patients with POI/DOR (diminished ovarian reserve) underwent next generation sequencing of the entire coding region of the BMP15 gene. The frequency of each identified BMP15 variant was then compared with that of the general population, taking into account the ethnicity of each individual. Screening of the entire coding region of the BMP15 gene allowed us the identification of 11 different variants, including one pathogenic non-sense variant. A total of 54 patients with POI (10.8%) carried out at least one BMP15 variant. With regard to missense variants, we observed a significant overrepresentation of two missense variants (2/10 missense variants) in our 500 POI patients when compared to the general or specific ethnic subgroups. Of interest is the identification of one homozygous POI subject with a loss-of-function variant. The results of the segregation analysis indicated that this variant was inherited by the healthy mother (menarche at 16 years of age, and physiological menopause at 53 years of age) and by the father. This epidemiological study suggests that the majority of heterozygous missense variants could be considered as benign variants, while the homozygous loss-of-function variant could be considered as pathogenic variant. Several missense variants should be considered as variants of uncertain significance, conferring a moderate risk with probable partial and very low penetrance and/or expressivity. However, it should be noted that these variants are only deleterious in the compound heterozygous or homozygous status.

Keywords: BMP15; Penetrance; Premature ovarian insufficiency.