Homozygous FIGLA missense variant in two Japanese sisters with primary ovarian insufficiency: Case reports and literature review.

Abstract

Background: FIGLA is a transcription factor gene which plays a critical role in folliculogenesis. Consistent with this, FIGLA variants have been identified in females with non-syndromic primary ovarian insufficiency (POI) in both autosomal-dominant and autosomal-recessive forms.

Case description: We encountered two Japanese sisters who had secondary or primary amenorrhea at 15 years of age. They were diagnosed as having non-syndromic primary ovarian insufficiency (POI) with hypergonadotropic hypoestrogenism and markedly low serum anti-Müllerian hormone values.

Outcome: Whole genome sequencing revealed a novel homozygous missense variant, NM_001004311.3:c.338A>G:p.(Tyr113Cys), in FIGLA essential for folliculogenesis in the two sisters. The parents were heterozygous for this variant, and the heterozygous mother had regular menses at 51 years of age. This variant was extremely rare in public databases, and was invariably assessed as deleterious by six prediction tools. Furthermore, the p.(Tyr113Cys)-FIGLA protein was assessed as "pathogenic" or "likely pathogenic" by protein structural predictions, and was evaluated as "destabilizing" or "decrease stability" by protein stability predictions.

Conclusion: The results, in conjunction with the data reported in the literature, imply that FIGLA variants account for a small but certain fraction of non-syndromic POI, and pose a question as to the relevance of FIGLA variants to an autosomal dominant form of POI, although FIGLA variants have been identified in both autosomal dominant and autosomal recessive forms of non-syndromic POI.