Whole-Genome Sequencing Reveals a Missense Variant in TUBA3C and a Pathogenic Stop-Gain Variant in GJB2 in a Family with Male Infertility

Infertility mostly affects more than one member in a family, increasing the chances that the underlying cause is genetic. WGS aids in the discovery of novel variations through a variety of processes that cause infertility. To identify potential infertility-causing variations using WGS, a comprehensive method for analyzing the entire genome, and to identify the underlying mechanisms that may be targeted for future disease management. For this purpose, we identified a family with two male members exhibiting clinically diagnosed infertility and one fertile member. Blood samples were collected and subjected to WGS for CNV, SNV, and Run of homozygosity (ROH) analysis. The resulting WGS data were analyzed using bioinformatics tools/pipelines to investigate potential variants. We identified missense and stop-gain variations in TUBA3C and GJB2 genes as probable causes of Deafness Infertility Syndrome. Importantly, the TUBA3C variant represents the third deleterious variant linked to azoospermia in this emerging infertility gene. The TUBA3C and GJB2 variants were in a 9 and 18 kb region of overlapping ROHs in 12-1 and 12-2 (chr13:19138488-19231863) and (chr13:20060678-20434605), respectively. Furthermore, 12-3 did not have an ROH overlapping either variant. Families with two or more male individuals presenting with infertility, along with healthy fertile controls, present a vital resource and opportunity to comprehensively identify the genetic landscape in the maintenance of male fertility. This study will help in the mechanistic understanding of Deafness Infertility Syndrome and provide for identifying with certainty causal variations among idiopathic patients, targets for management, and the development of future therapy for male infertility.