Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility

Hum Mutat. 2020 May;41(5):998-1011. doi: 10.1002/humu.23993. Epub 2020 Feb 12.


Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.

Keywords: CEP78; cilia; cone-rod dystrophy with hearing loss (CRDHL); founder; male infertility; missense.

Publication types

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

MeSH terms

  • Adolescent
  • Alleles*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics*
  • Cilia / metabolism
  • Cilia / ultrastructure
  • Cone-Rod Dystrophies / diagnosis
  • Cone-Rod Dystrophies / genetics*
  • DNA Mutational Analysis
  • Exome Sequencing
  • Female
  • Fibroblasts / metabolism
  • Founder Effect*
  • Genotype
  • Hearing Loss / diagnosis
  • Hearing Loss / genetics*
  • Humans
  • Infertility, Male / diagnosis
  • Infertility, Male / genetics*
  • Male
  • Middle Aged
  • Models, Molecular
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Protein Conformation
  • Structure-Activity Relationship
  • Syndrome


  • CEP78 protein, human
  • Cell Cycle Proteins