Joubert syndrome: Genotyping a Northern European patient cohort

Hester Y. Kroes*, Glen R. Monroe, Bert van der Zwaag, Karen J. Duran, Carolien G. de Kovel, Mark J. van Roosmalen, Magdalena Harakalova, Ies J. Nijman, Wigard P. Kloosterman, Rachel H. Giles, Nine V A M Knoers, Gijs van Haaften

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)214-220
Number of pages7
JournalEuropean Journal of Human Genetics
Issue number2
Publication statusPublished - 1 Feb 2016


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