Biallelic mutations in <i>CFAP65</i> lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations.

Abstract

The genetic causes for most male infertility due to severe asthenozoospermia remain unclear. Our objective was to identify unknown genetic factors in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families. We performed whole exome sequencing of 47 individuals with severe asthenozoospermia from 45 unrelated families. Mutation screening was performed in a control cohort of 637 individuals, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia and 223 fertile controls. Ultrastructural and immunostaining analyses of patients' spermatozoa were performed to characterise the effect of variants. One homozygous non-sense mutation (NM_194302, c.G5341T:p.E1781X), two compound heterozygous mutations (c.C2284T:p.R762X and c.1751delC:p.P584fs) and two compound heterozygous mutations (c.5714_5721del:p.L1905fs and c.C3021A:p.N1007K) were identified in <i>CFAP65</i> of three individuals with completely immotile spermatozoa, respectively. No biallelic deleterious variants of <i>CFAP65</i> were detected in the control cohort of 637 individuals. Ultrastructural and immunostaining analyses of spermatozoa from two patients showed highly aberrant sperm morphology with severe defects such as acrosome hypoplasia, disruption of the mitochondrial sheath and absence of the central pair complex. To the best of our knowledge, we are the first to report that <i>CFAP65</i> mutations may cause spermatozoa to be completely immotile.