Whole Exome Sequencing of a Consanguineous Turkish Family Identifies a Mutation in GTF2H3 in Brothers With Spermatogenic Failure

Abstract

In this case report we describe our investigation into the genetic cause of infertility due to idiopathic nonobstructive azoospermia in a consanguineous Turkish family. We extracted DNA from blood and applied whole exome sequencing on 4 infertile brothers in this family diagnosed with oligo- and azoospermia. Standard bioinformatics analysis pipelines were run including alignment to the reference genome, variant calling, and quality control filtering. Potentially pathogenic variants were identified and prioritized using genetic variant annotation software and public variant frequency databases, followed by validation with Sanger sequencing. A nonsynonymous variant in "general transcription factor TFIIH subunit 3" (GTF2H3) was identified in this consanguineous family. This variant in chromosome 12 (12chr: 124144111 T>C, p.Ser222Pro) of GTF2H3 represents a likely a disease-causing mutation as it is predicted to be damaging, rare, segregates with the disease, and is highly evolutionarily conserved. Familial segregation analysis of the variant showed that it was present as a homozygous mutation in the brothers with nonobstructive azoospermia, and heterozygous mutation in the oligospermic brothers. We propose a mechanism by which this variant leads to deficits in Vitamin A signaling, which is essential for spermatogenesis.