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Updated: Feb 9, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

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A homozygous FANCM frameshift pathogenic variant causes male infertility

Hao Yin1, Hui Ma1, Sajjad Hussain1

  • 1Hefei National Laboratory for Physical Sciences at Microscale, The First Affiliated Hospital of USTC, USTC-SJH Joint Center for Human Reproduction and Genetics, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei, 230027, China.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|June 14, 2018
PubMed
Abstract

Insights

Pathogenic variants in the FANCM gene cause male infertility in humans, leading to conditions like oligoasthenospermia and azoospermia. This study validates FANCM as a cause of male infertility, a novel phenotype for this gene.

Area of Science:

  • Genetics
  • Reproductive Biology
  • Human Health

Background:

  • Fanconi anemia (FA) genes, including FANCM, are crucial for spermatogenesis.
  • While Fancm disruption in mice causes male infertility, the effect of FANCM pathogenic variants (PV) in humans remained uncharacterized.

Purpose of the Study:

  • To investigate the role of FANCM pathogenic variants (PV) in male infertility within a Pakistani family.
  • To validate a specific homozygous FANCM PV (c.1946_1958del, p.P648Lfs*16) as the cause of infertility in affected brothers.

Main Methods:

  • Exome and Sanger sequencing were employed for variant screening.
  • DNA interstrand crosslink (ICL) sensitivity assays were performed on patient lymphocytes.
  • A mouse model (FancmΔC/ΔC) was generated for functional analysis of spermatogenesis.

Main Results:

  • The identified FANCM PV led to increased ICL sensitivity in patient lymphocytes and mouse spermatogonia.
  • FancmΔC/ΔC mice exhibited significant spermatogenic failure, including germ cell loss and maturation arrest.
  • No bone marrow failure or cancer was observed in patients or the mouse model.

Conclusions:

  • Biallelic FANCM PVs result in male infertility, a previously unrecognized phenotype in humans.
  • This study establishes a direct link between FANCM gene defects and male reproductive failure.
Keywords:
FANCM PVInterstrand crosslink sensitivity Fanconi anemiaMale infertilitySpermatogenic failure

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