Novel biallelic DNHD1 variants associated with male infertility with severe MMAF phenotype.

Multiple morphological abnormalities of the sperm flagella (MMAF), characterized by severe morphological sperm defects, such as absent, short, irregular caliber, and coiled flagella with extreme asthenoteratozoospermia, are the most prevalent cause of human male infertility. Previous studies have identified several genes linked to MMAF; however, the increasing incidence of infertility indicates that most affected individuals remain undiagnosed, prompting further investigation to uncover novel mutations and genes. Whole-exome sequencing (WES) was conducted on a consanguineous infertile family from Pakistan to investigate the potential monogenic inheritance pattern in individuals affected by asthenoteratozoospermia. WES identified novel homozygous variants (c.A4457G; p.K1486R, and c.C10624T; p.R3542*) in dynein heavy chain domain 1 ( DNHD1 ) in the proband and his affected brother. Semen analysis revealed a low progressive motility and severe MMAF in both siblings. Hematoxylin and eosin staining, immunofluorescence, and transmission electron microscopy unveiled an abnormal axoneme structure characterized by missing central pairs, disorganized microtubule duplets, and severe mitochondrial sheath defects, which led to the low sperm progressive motility and infertility in the affected siblings. This study identified a novel biallelic nonsense variant in DNHD1 that caused MMAF in a Pakistani population, endorsing previous findings and expanding the spectrum of potential DNHD1 variants in the pathogenesis of asthenoteratozoospermia.