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

Joubert syndrome: genotyping a Northern European patient cohort

Hester Y Kroes  1 , Glen R Monroe  1 , Bert van der Zwaag  1 , Karen J Duran  1 , Carolien G de Kovel  1 , Mark J van Roosmalen  1 , Magdalena Harakalova  1 , Ies J Nijman  1 , Wigard P Kloosterman  1 , Rachel H Giles  2 , Nine V A M Knoers  1 , Gijs van Haaften  1
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Joubert syndrome: genotyping a Northern European patient cohort

Hester Y Kroes et al. Eur J Hum Genet. 2016 Feb.

Abstract

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.

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