STAG3 truncating variant as the cause of primary ovarian insufficiency

Abstract

Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development. Multipoint parametric linkage analysis was performed. Whole-exome sequencing was done on the proband. Linkage analysis identified a locus on chromosome 7 where exome sequencing successfully identified a homozygous two base pair duplication (c.1947_48dupCT), leading to a truncated protein p.(Y650Sfs*22) in the STAG3 gene, confirming it as the cause of POI in this family. Exome sequencing combined with linkage analyses offers a powerful tool to efficiently find novel genetic causes of rare, heterogeneous disorders, even in small single families. This is only the second report of a STAG3 variant; the first STAG3 variant was recently described in a phenotypically similar family with extreme POI. Identification of an additional family highlights the importance of STAG3 in POI pathogenesis and suggests it should be evaluated in families affected with POI.

Figure 1

Segregation of STAG3 c.1947_48dupCT resulting in STAG3 p.(Y650Sfs*22) in a Lebanese consanguineous family. Electropherograms generated by Sanger sequencing. Proband (II-1) is indicated by an arrow. Unaffected sister (II-3) is homozygous for the reference sequence (Ref), affected sisters (II-1 and II-2) are STAG3 c.1947_48dupCT homozygous (CT duplication is depicted in a box) and the parents are heterozygous.

Figure 2

Linkage analysis of a Lebanese consanguineous family presenting with primary ovarian insufficiency. Linkage plot showing logarithm of odds (LOD) scores across the whole genome. Arrow indicates linkage to STAG3.