Joubert syndrome: genotyping a Northern European patient cohort

Eur J Hum Genet. 2016 Feb;24(2):214-20. doi: 10.1038/ejhg.2015.84. Epub 2015 Apr 29.


Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with >20 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis*
  • Abnormalities, Multiple / epidemiology
  • Abnormalities, Multiple / genetics*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Vesicular Transport
  • Adolescent
  • Cerebellum / abnormalities*
  • Child
  • Child, Preschool
  • Cytoskeletal Proteins
  • Eye Abnormalities / diagnosis*
  • Eye Abnormalities / epidemiology
  • Eye Abnormalities / genetics*
  • Female
  • Genetic Counseling*
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Kidney Diseases, Cystic / diagnosis*
  • Kidney Diseases, Cystic / epidemiology
  • Kidney Diseases, Cystic / genetics*
  • Male
  • Membrane Proteins / genetics
  • Pathology, Molecular*
  • Proteins / genetics
  • Retina / abnormalities*
  • Young Adult


  • AHI1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • B9D1 protein, human
  • CC2D2A protein, human
  • CPLANE1 protein, human
  • Cytoskeletal Proteins
  • Membrane Proteins
  • Proteins
  • TMEM67 protein, human

Supplementary concepts

  • Agenesis of Cerebellar Vermis