Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome

Hum Mutat. 2020 Dec;41(12):2179-2194. doi: 10.1002/humu.24127. Epub 2020 Nov 1.


Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss-of-function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense-mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF-variants cause a ciliopathy with features of Joubert syndrome.

Keywords: CBY1; Joubert syndrome; ciliopathy; primary cilia defect; whole exome sequencing; zebrafish.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Adolescent
  • Animals
  • Carrier Proteins / genetics*
  • Cerebellum / abnormalities*
  • Cerebellum / diagnostic imaging
  • Cerebellum / pathology
  • Child
  • Child, Preschool
  • Cilia / metabolism
  • Cilia / pathology
  • Ciliopathies / diagnostic imaging
  • Ciliopathies / genetics*
  • Ciliopathies / pathology
  • Eye Abnormalities / diagnostic imaging
  • Eye Abnormalities / genetics*
  • Eye Abnormalities / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Homozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Kidney Diseases, Cystic / diagnostic imaging
  • Kidney Diseases, Cystic / genetics*
  • Kidney Diseases, Cystic / pathology
  • Magnetic Resonance Imaging
  • Male
  • Mutation / genetics*
  • Nuclear Proteins / genetics*
  • Pedigree
  • Phenotype
  • Retina / abnormalities*
  • Retina / diagnostic imaging
  • Retina / pathology
  • Smoothened Receptor / metabolism
  • Young Adult
  • Zebrafish / genetics


  • CBY1 protein, human
  • Carrier Proteins
  • Nuclear Proteins
  • SMO protein, human
  • Smoothened Receptor

Supplementary concepts

  • Agenesis of Cerebellar Vermis