Novel compound heterozygous variants of DNAH17 in a Chinese infertile man with multiple morphological abnormalities of sperm flagella

Abstract

Multiple morphological abnormalities of the sperm flagellum (MMAF) have been reported to be an important cause of male infertility and reflect a heterogeneous genetic disorder. Previous studies have identified dozens of candidate pathogenic genes for MMAF, but the aetiology in approximately 50% of cases remains unexplained. The present study aimed to identify novel potentially pathogenic gene variants of MMAF. A Chinese family with a 32‐year‐old infertile proband presenting with MMAF was recruited, and sperm morphology of the patient was examined by Papanicolaou staining. Whole exome sequencing was performed on the proband and Sanger sequencing was used to identify genetic variants in the family. The frequencies of variants were assessed using public databases and the effects on protein structure and function were predicted by online bioinformatics tools. The patient exhibited asthenozoospermia and a MMAF phenotype. Novel compound heterozygous variants (c.5368C > T, p.R1790C and c.13183C > T, p.R4395W) of the DNAH17 gene were identified in the patient, and showed autosomal recessive inheritance in this family. These variants were very rare in the GnomAD database. The two mutated amino acids were located in a highly conserved region of the DNAH17 protein. In silico analysis revealed that the compound heterozygous variants may compromise the function of DNAH17. Our findings expand upon the spectrum of pathogenic DNAH17 variants that are responsible for MMAF, and provide new knowledge for genetic counselling of male infertility due to MMAF.

Clinical detection, diagnosis and treatment of morphological abnormalities of sperm flagella: A review of literature

“…A recent study has reported that FSIP2 mutant sperm show a globozoospermia phenotype in addition to flagella defects, and FSIP2 localizes in the acrosome and interacts with proteins associated with acrosome formation, indicating the potential function of FSIP2 in acrosome development ( Zheng et al, 2022 ), which is consistent with single-cell RNA-seq data ( Fang et al, 2021 ). FSIP2 has been demonstrated to interact with two other FS proteins, namely, AKAP3 and AKAP4, which are encoded by MMAF causative genes ( Zhang G. et al, 2021 ; Liu Z. et al, 2022 ). In 2005, the possible relationship between DFS and partial deletions in the AKAP3 and AKAP4 genes was revealed ( Baccetti et al, 2005b ).…”