Novel STAG3 variant causes oligoasthenoteratozoospermia with high sperm aneuploidy rate

Premature ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) are the most severe forms of infertility. Pathogenic variants in a number of genes cause both disorders in siblings. One of them is STAG3, which encodes a meiosis-specific subunit of a cohesin complex. Here, we searched for genetic cause of oligoasthenoteratozoospermia (OAT) and POI within one family.

The proband was a 16-year-old girl with secondary amenorrhea. She was diagnosed with hypergonadotropic hypogonadism and streak ovaries. She had normal karyotype 46,XX and no premutation in FMR1 gene. Her 28-year-old brother was diagnosed with severe oligoasthenoteratozoospermia (OAT) syndrome. The aneuploidy rate in his sperm was assessed by FISH assay and appeared to be extremely high with only 5% of morphologically normal spermatozoa being haploid. He had normal karyotype 46,XY and no AZF microdeletions.

Whole exome sequencing identified two likely pathogenic heterozygous truncating variants in STAG3 gene, prevously described p.Arg926Ter and novel p.Glu1184Ter. Sanger sequencing showed that both the patient and her brother were compound heterozygotes.

In this study, we suggest the association of the identified variants in STAG3 gene with OAT syndrome and POI and describe the third familial case of STAG3-related infertility.