A homozygous FANCM frameshift pathogenic variant causes male infertility

Hao Yin, Hui Ma, Sajjad Hussain, Huan Zhang, Xuefeng Xie, Long Jiang, Xiaohua Jiang, Furhan Iqbal, Ihtisham Bukhari, Hanwei Jiang, Asim Ali, Liangwen Zhong, Tao Li, Suixing Fan, Beibei Zhang, Jianing Gao, Yang Li, Jabeen Nazish, Teka Khan, Manan KhanMuhammad Zubair, Qiaomei Hao, Hui Fang, Jun Huang, Mahmoud Huleihel, Jiahao Sha, Tej K. Pandita, Yuanwei Zhang, Qinghua Shi

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


Purpose: Fanconi anemia (FA) genes play important roles in spermatogenesis. In mice, disruption of Fancm impairs male fertility and testicular integrity, but whether FANCM pathogenic variants (PV) similarly affect fertility in men is unknown. Here we characterize a Pakistani family having three infertile brothers, two manifesting oligoasthenospermia and one exhibiting azoospermia, born to first-cousin parents. A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility. Our objective is to validate that FANCM p.P648Lfs*16 is the PV causing infertility in this family. Methods: Exome and Sanger sequencing were used for PV screening. DNA interstrand crosslink (ICL) sensitivity was assessed in lymphocytes from patients. A mouse model carrying a PV nearly equivalent to that in the patients (FancmΔC/ΔC) was generated, followed by functional analysis in spermatogenesis. Results: The loss-of-function FANCM PV increased ICL sensitivity in lymphocytes of patients and FancmΔC/ΔC spermatogonia. Adult FancmΔC/ΔC mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules. In addition, neither bone marrow failure nor cancer/tumor was detected in all the patients or adult FancmΔC/ΔC mice. Conclusion: These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV.

Original languageEnglish (US)
Pages (from-to)62-70
Number of pages9
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 1 2019


  • Interstrand crosslink sensitivity Fanconi anemia
  • Male infertility
  • Spermatogenic failure

ASJC Scopus subject areas

  • Genetics(clinical)


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