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

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54 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)214-220
Aantal pagina's7
TijdschriftEuropean Journal of Human Genetics
Nummer van het tijdschrift2
StatusGepubliceerd - 1 feb. 2016
Extern gepubliceerdJa


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