ORPHA: 475; DO: 0110986;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p13.2 | Joubert syndrome 17 | 614615 | Autosomal recessive | 3 | CPLANE1 | 614571 |
A number sign (#) is used with this entry because Joubert syndrome-17 (JBTS17) is caused by compound heterozygous mutation in the C5ORF42 gene (CPLANE1; 614571) on chromosome 5p13.
Mutation in the C5ORF42 gene can also cause orofaciodigital syndrome VI (OFD6; 277170), a disorder with overlapping features.
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Joubert et al. (1969) described 4 French Canadian sibs, born of distantly related parents, with a severe neurologic disorder characterized by episodic hyperpnea, abnormal eye movements, ataxia, and global psychomotor retardation. Partial or complete agenesis of the cerebellar vermis was demonstrated by autopsy or pneumoencephalogram. One patient also had an occipital meningomyelocele. The oldest living sib was 8 years old.
Srour et al. (2012) reported 10 patients from 7 French Canadian families with Joubert syndrome. Two sibs were part of the original family described by Joubert et al. (1969). All patients showed global developmental delay, with the onset of independent walking between 30 months and 8 years of age. Cognitive impairment was present in all individuals but was variable, ranging from borderline intelligence to mild intellectual disability. Most also showed oculomotor apraxia and breathing abnormalities, mainly episodic hyperventilation. Two individuals had limb abnormalities; 1 had preaxial and postaxial polydactyly, and another had syndactyly of the third and fourth fingers on 1 hand. Brain MRI showed the molar tooth sign in all patients examined. None had evidence of retinal or kidney involvement.
In a comprehensive study of 279 patients from 232 unrelated families with Joubert syndrome in whom a genetic basis was determined by molecular analysis of 27 candidate genes, Bachmann-Gagescu et al. (2015) found a significant association between mutations in the C5ORF42 gene and polydactyly (odds ratio (OR) of 2.7).
The transmission pattern of Joubert syndrome-17 in the families reported by Srour et al. (2012) was consistent with autosomal recessive inheritance.
In affected individuals from 7 French Canadian families with Joubert syndrome-17, Srour et al. (2012) identified 6 different potentially pathogenic mutations in the C5ORF42 gene (614571.0001-614571.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Three of the mutations were found in multiple families, and haplotype analysis showed that each was linked to a distinct haplotype. The higher frequency of these mutations in the Lower St. Lawrence region might be explained by a founder effect with the coincidental occurrence of the 3 mutations in the same group of settlers, or by multiple regional founder effects corresponding to sequential pioneer fronts.
Using fetal ultrasound biomicroscopy, Damerla et al. (2015) screened N-ethylnitrosourea-generated mouse mutants for congenital heart disease and identified 'heart under glass' (hug) mutant mice with agenesis of the rib cage. Hug mutants had multiple developmental defects that caused prenatal mortality, including skeletal dysplasia, craniofacial defects, polydactyly, cystic kidneys, and cerebellar hypoplasia. Hug mutants and cultured fibroblasts showed perturbed hedgehog signaling (see SHH, 600725). However, hug cochlea had normal stereocilia and kinocilia, and hug neural tube had normal dorsoventral patterning. Damerla et al. (2015) identified the hug mutation as a homozygous 757T-C transition in the C5orf42 gene that results in a ser253-to-phe (S253F) substitution at a highly conserved residue in the Jbts17 protein.
Bachmann-Gagescu, R., Dempsey, J. C., Phelps, I. G., O'Roak, B. J., Knutzen, D. M., Rue, T. C., Ishak, G. E., Isabella, C. R., Gorden, N., Adkins, J., Boyle, E. A., de Lacy, N., and 17 others. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J. Med. Genet. 52: 514-522, 2015. [PubMed: 26092869] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103087]
Damerla, R. R., Cui, C., Gabriel, G. C., Liu, X., Craige, B., Gibbs, B. C., Francis, R., Li, Y., Chatterjee, B., San Agustin, J. T., Eguether, T., Subramanian, R., Witman, G. B., Michaud, J. L., Pazour, G. J., Lo, C. W. Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies. Hum. Molec. Genet. 24: 3994-4005, 2015. [PubMed: 25877302] [Full Text: https://doi.org/10.1093/hmg/ddv137]
Joubert, M., Eisenring, J. J., Robb, J. P., Andermann, F. Familial agenesis of the cerebellar vermis: a syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 19: 813-825, 1969. Note: Reprinted in J. Child Neurol. 14: 554-564, 1999. [PubMed: 5816874] [Full Text: https://doi.org/10.1212/wnl.19.9.813]
Srour, M., Schwartzentruber, J., Hamdan, F. F., Ospina, L. H., Patry, L., Labuda, D., Massicotte, C., Dobrzeniecka, S., Capo-Chichi, J.-M., Papillon-Cavanagh, S., Samuels, M. E., Boycott, K. M., Shevell, M. I., Laframboise, R., Desilets, V., FORGE Canada Consortium, Maranda, B., Rouleau, G. A., Majewski, J., Michaud, J. L. Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am. J. Hum. Genet. 90: 693-700, 2012. [PubMed: 22425360] [Full Text: https://doi.org/10.1016/j.ajhg.2012.02.011]