Investigating the Role of Structural Variation in Male Infertility

Abstract

Infertility affects approximately one in six couples globally, with male factors contributing to roughly half of all cases. Although chromosomal abnormalities such as Klinefelter’s syndrome and Y chromosome microdeletions are well-established causes of male infertility (MI), nearly 40% of cases remain idiopathic. The role of structural variants (SVs) and dominant inheritance pattern has been understudied, primarily due to technical limitations in identifying SVs and the lack of patient-parent trio analyses required to investigate dominant de novo variants. In this thesis, we performed whole-genome sequencing (WGS) on 216 patients with idiopathic azoospermia and their parents to investigate SVs across different inheritance models, with a particular focus on the dominant model. Additionally, whole-exome sequencing (WES) was conducted on 234 additional patients with azoospermia. In these cohorts, we identified several SVs that clearly explained the patients' phenotypes, as well as numerous potentially causative SVs that revealed novel candidate male infertility genes and loci. This study demonstrates that WGS is an effective tool for studying SVs and significantly advances our understanding of the genetic basis of male infertility, particularly regarding the contribution of SVs.