Anatomy

Compound heterozygosity

Phenotype

Pathology

Exome sequencing

Infertility

Immunostaining

Haploinsufficiency

Biology

Gene

Immunohistochemistry

Andrology

Immunology

Male infertility

Asthenozoospermia

Azoospermia

Hypoplasia

Acrosome

Pregnancy

Mutation

Sperm

Genetics

Medicine

Journal of Medical Genetics

Background The genetic causes for most male infertility due to severe asthenozoospermia remain unclear. Objective Our objective was to identify unknown genetic factors in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families. Methods 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. Results 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 CFAP65 of three individuals with completely immotile spermatozoa, respectively. No biallelic deleterious variants of CFAP65 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. Conclusion To the best of our knowledge, we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile.

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

Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations