A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella

Clin Genet. 2019 Dec;96(6):541-548. doi: 10.1111/cge.13644. Epub 2019 Oct 3.


Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare autosomal recessive inherited disorder associated with male infertility. To date, 14 genetic causative genes have been identified in MMAF, which can only explain the genetic causes of ~60% of MMAF cases. Here, we report a man with primary infertility, who had a typical MMAF phenotype. Whole-exome sequencing (WES) was performed on the patient and a homozygous mutation (c. 2675 G>A [p. Trp892*]) was identified in cilia and flagella-associated protein 65 (CFAP65) gene, which is primarily expressed in the testis. Another loss-of-function mutation of CFAP65 has been detected in a MMAF patient, and the orthologue of CFAP65 also plays a vital role in sperm motility in chickens. Our experimental observations on human subjects suggested that CFAP65 is involved in sperm flagellum structure and assembly and that loss-of-function mutations could lead to male infertility in humans by causing the MMAF phenotype.

Keywords: CFAP65; MMAF; WES; gene mutations; male infertility.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Asthenozoospermia / genetics
  • Asthenozoospermia / pathology
  • Case-Control Studies
  • Codon, Nonsense / genetics
  • Female
  • Homozygote
  • Humans
  • Infertility, Male / genetics*
  • Loss of Function Mutation
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • RNA-Binding Proteins / genetics*
  • Semen / metabolism
  • Sperm Tail / pathology*
  • Sperm Tail / ultrastructure
  • Testis / metabolism


  • CFAP65 protein, human
  • Codon, Nonsense
  • Membrane Proteins
  • RNA-Binding Proteins