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

Islam Uddin1,2, Iqra Zafar1,2, Cao-Ling Xu1,2

  • 1Center for Reproduction and Genetics, Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.

Asian Journal of Andrology
|November 11, 2025
PubMed

Insights

Multiple morphological abnormalities of the sperm flagella (MMAF) cause male infertility. This study identified a novel DNHD1 gene variant responsible for MMAF in a Pakistani family, revealing sperm structure defects and expanding understanding of infertility causes.

Area of Science:

  • Genetics
  • Reproductive Biology
  • Molecular Biology

Background:

  • Multiple morphological abnormalities of the sperm flagella (MMAF) are a primary cause of male infertility, characterized by severe defects like absent or coiled flagella.
  • Despite identified genes, many male infertility cases remain undiagnosed, necessitating further research into novel genetic mutations.
  • Asthenoteratozoospermia, a severe sperm defect, significantly impacts fertility, highlighting the need for genetic diagnostics.

Purpose of the Study:

  • To investigate the genetic basis of asthenoteratozoospermia in a consanguineous Pakistani family.
  • To identify novel gene mutations responsible for multiple morphological abnormalities of the sperm flagella (MMAF).
  • To elucidate the pathogenic mechanism linking genetic variants to sperm dysfunction and infertility.

Main Methods:

  • Whole-exome sequencing (WES) was performed on affected individuals from an infertile Pakistani family.
  • Semen analysis was conducted to assess sperm parameters, including motility and morphology.
  • Advanced microscopy techniques (H&E staining, immunofluorescence, TEM) were used to examine sperm ultrastructure.

Main Results:

  • Novel homozygous variants (c.A4457G; p.K1486R and c.C10624T; p.R3542*) in the dynein heavy chain domain 1 (DNHD1) gene were identified.
  • Affected siblings exhibited severe MMAF, low progressive motility, and abnormal sperm axoneme structure, including missing central pairs and disorganized microtubule duplets.
  • Mitochondrial sheath defects were also observed, contributing to impaired sperm function and infertility.

Conclusions:

  • A novel biallelic nonsense variant in DNHD1 causes MMAF and asthenoteratozoospermia in the Pakistani population.
  • This finding expands the spectrum of DNHD1 variants associated with male infertility.
  • The study underscores the importance of genetic investigation in diagnosing and understanding male infertility.
Keywords:
asthenoteratozoospermiabiallelic mutationconsanguinitymale infertilitywhole-exome sequencing

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