Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency

Primary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient.

An adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelect^XT DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing.

Two rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants.

Our results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency.