Autosomal Mutations and Spermatogenic Failure

Abstract

Abstract Male infertility is commonly due to an impairment in the production of viable sperm, capable of fertilisation. Spermatogenic failure can manifest in its most severe form by an absence of mature sperm or, more often, by a reduction in sperm counts, as an isolated phenotype or in combination with abnormalities in sperm motility and morphology. In only a fraction of patients with primary spermatogenic failure can an underlying genetic cause be identified, such as karyotype abnormalities and Y chromosome microdeletions. However, a small number of autosomal genes harbour rare variants/mutations with strong evidence of their impact in primary spermatogenic failure in otherwise healthy men ( SYCP3 , NR5A1 , DMRT1 , CATSPER , DNAI1 , DNAH5 , DNAH11 , SLC26A8 , AURKC , SPATA16 , DPY19L2 , KLHL10 and SEPT12 ). Even though the clinical relevance of the majority of these variants is still uncertain, they represent promising markers for spermatogenesis deficits. Key Concepts: Spermatogenesis is an intricate process and a large number of genes on the autosomes are involved. The etiopathogenesis of severe spermatogenic failure in otherwise healthy men is complex and still largely unknown. A highly penetrant genetic variant resulting in male infertility should be rare in a population. Validation of potentially deleterious variants must rely on the analysis of a large number of patients, replication in cohorts of different ethnicity, familial data and functional assays. Spermatogenic failure may result from the disturbance of many different processes (gonadal formation and maintenance, meiosis and morphological differentiation of gametes).