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

BACKGROUND

is a transcription factor gene which plays a critical role in folliculogenesis. Consistent with this, 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 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 variants account for a small but certain fraction of non-syndromic POI, and pose a question as to the relevance of variants to an autosomal dominant form of POI, although variants have been identified in both autosomal dominant and autosomal recessive forms of non-syndromic POI.