Uncovering Genetic Factors Involved in Men Infertility

Introduction:

Genetic etiologies of male infertility remain mostly unclear, and only limited genetic tests are offered to uncover the genetic etiology of infertile men and their chances of fathering children.

Aim:

Identify new genetic factors involved in men fertility.

Materials:

From our database of 1000 men, we chose four families with a history of familial infertility, familial consanguinity, and similar spermatogenetic impairment of spermatocyte arrest determined after careful cytological and molecular analysis. Next generation sequencing (NGS) of exomes or genomes was followed by robust procedures to align raw reads, kinship confirmation, and comprehensive mutations annotations. We validated the suspected causative mutations by Sanger sequencing, familial segregation, screening patients and controls from same ethnicity (n=265), and screening in-house NGS-database (n=916).

Results:

While the four families shared identical testicular impairment of spermatocyte maturation arrest, we identified four different novel causative mutations in three different genes. These genes are exclusively expressed, or highly specific to men and mice testis. Screening fertile and infertile men with RFLP (restriction fragment length polymorphism) methodology identified two additional patients homozygote for one of the mutations. Available mice gene knockouts for two of the genes have an equivalent infertility phenotype of infertility due to spermatocyte maturation arrest as our patients.

Conclusions:

Our findings of causative mutations in three different genes associated with different meiosis pathways that lead to a single testicular pathology, demonstrate the genetic complexity of men infertility. These results could pave the way for new diagnostic and treatment procedures for infertile men.