STAG3 truncating variant as the cause of primary ovarian insufficiency.

Polona Le Quesne Stabej,Hywel J Williams,Horia C Stanescu,Robert Kleta,Gerard S Conway,Chiara Bacchelli,Chela James,Helen L Storr,Maria Bitner-Glindzicz,Mehmet Tekman,Francesco Lescai,Louise Ocaka

doi:10.1038/ejhg.2015.107

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.

Highlights

Primary ovarian insufficiency (POI) is defined as a post pubertal hypergonadotropic hypogonadism in women under the age of 40 years
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
It has recently been reported that POI can result from truncating variant in stromal antigene 3 gene (STAG3), which encodes a subunit of cohesin; a large ring-shaped protein complex essential for proper pairing and segregation of chromosomes during meiosis, which is required for gametogenesis and fertility.[5]

Summary

Introduction

Primary ovarian insufficiency (POI) is defined as a post pubertal hypergonadotropic hypogonadism in women under the age of 40 years. A growing number of genes have been identified, which harbour variants that affect function associated with POI. Known genes causing ovarian insufficiency are known to account for less than 5% of cases; family studies suggest that 20–30% of women with POI have an affected relative.[8] As mentioned above, it has recently been reported that POI can result from truncating variant in stromal antigene 3 gene (STAG3), which encodes a subunit of cohesin; a large ring-shaped protein complex essential for proper pairing and segregation of chromosomes during meiosis, which is required for gametogenesis and fertility.[5] In mammals, there are four known meiosis-specific cohesin core subunits: SMC1β, RAD21L, REC8 and STAG3. Rec[8] null mice of both sexes have germ cell failure and are sterile and Rad21l‐deficient females are fertile but develop an age‐dependent sterility.[10,11]

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Conclusion