Joubert syndrome: genotyping a Northern European patient cohort.
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.
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Hester Y
HY
Kroes
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Glen R
GR
Monroe
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Bert
B
van der Zwaag
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Karen J
KJ
Duran
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Carolien G
http://orcid.org/0000-0002-7818-1396
CG
de Kovel
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Mark J
MJ
van Roosmalen
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Magdalena
M
Harakalova
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Ies J
IJ
Nijman
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Wigard P
WP
Kloosterman
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
Rachel H
http://orcid.org/0000-0001-9133-2008
RH
Giles
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Nine V A M
NV
Knoers
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Gijs
G
van Haaften
D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D033942:Adaptor Proteins, Vesicular Transport; D000293:Adolescent; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D005124:Eye Abnormalities / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005817:Genetic Counseling; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D052177:Kidney Diseases, Cystic / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D057089:Pathology, Molecular; D011506:Proteins / Q000235:genetics; D012160:Retina / Q000002:abnormalities*; D055815:Young Adult
C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C000592877:B9D1 protein, human; C528701:CC2D2A protein, human; C572460:CPLANE1 protein, human; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D011506:Proteins; C468846:TMEM67 protein, human