Whole-exome sequencing identifies rare recessive variants in azoospermia patients from consanguineous Pakistani families.

Azoospermia, a severe form of male infertility characterized by the complete absence of sperm in the ejaculate, affects about 1% of the male population, with most cases attributed to nonobstructive azoospermia (NOA) caused by gametogenic failure. NOA has various genetic origins, including chromosomal abnormalities, Y chromosome microdeletions, and monogenic mutations. Although whole-exome sequencing (WES) has identified over thirty candidate genes associated with NOA, the genetic causes of most cases have yet to be elucidated. In our study, we selected seven consanguineous families diagnosed with azoospermia from a total of 21 male infertile families recruited from the rural area of Pakistan. Blood samples were collected from both patients and fertile controls for DNA extraction, followed by WES to identify potential causative recessive monogenic variants linked to male infertility. We successfully identified five deleterious variants among five of the seven families, including three missense biallelic substitutions in WWC2, RPL10L, and SOHLH1, a hemizygous deletion in ESX1, and a homozygous deletion in TXNDC2, which have potentially pathogenic relevance to the azoospermia of human male infertility. These novel findings enhance our understanding of the molecular mechanisms underlying the complex etiology of azoospermia, offering valuable insights for genetic counseling and diagnostics and paving the way for future therapeutic approaches.