ORPHA: 475; DO: 0110993;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.31 | Joubert syndrome 24 | 616654 | Autosomal recessive | 3 | TCTN2 | 613846 |
A number sign (#) is used with this entry because of evidence that Joubert syndrome-24 (JBTS24) is caused by homozygous mutation in the TCTN2 gene (613846) on chromosome 12q24.
Joubert syndrome-24 (JBTS24) is an autosomal recessive ciliopathy characterized by delayed psychomotor development associated with cerebellar hypoplasia manifest as the molar tooth sign on brain imaging. Additional variable features include hypotonia, abnormal eye movements, and postaxial polydactyly (summary by Huppke et al., 2015).
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Sang et al. (2011) reported 7 patients from 4 unrelated families with Joubert syndrome. Features included cerebellar vermis aplasia, the molar tooth sign on brain imaging, hypotonia, and delayed psychomotor development. More variable features included nystagmus, talipes equinovarus, and spasticity. None of the patients had renal abnormalities.
Huppke et al. (2015) reported a 7.5-year-old Turkish boy, born of consanguineous parents, with a neurodevelopmental disorder consistent with Joubert syndrome. At birth, the patient was noted to have postaxial hexadactyly of all 4 extremities, but no other dysmorphic features. He had hypotonia and severely delayed psychomotor development with inability to speak more than 2 words. He also had nystagmus and hyperopia. Brain MRI showed polymicrogyria, pachygyria, cerebellar hypoplasia with the molar tooth sign, and myelination defects. He learned to walk at age 7 years, but showed spasticity, hyperreflexia, ataxia, and dysmetria. Two previous pregnancies of the parents ended in early abortions within the first trimester, and a subsequent pregnancy was terminated after brain and digital anomalies were detected on prenatal ultrasound.
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 TCTN2 gene and encephalocele (odds ratio (OR) of 13.6) and polydactyly (OR of 18.7).
The transmission pattern of JBTS24 in the family reported by Huppke et al. (2015) was consistent with autosomal recessive inheritance.
In 6 patients from 3 unrelated families with JBTS24, Sang et al. (2011) identified 3 different homozygous mutations in the TCTN2 gene (613846.0002-613836.0004). The mutations were found by genome linkage analysis of families with ciliopathies and by targeting candidate genes identified through modeled network disease pathways focused on ciliopathies. Functional studies of the variants were not performed.
In a 7.5-year-old Turkish boy, born of consanguineous parents, with JBTS24, Huppke et al. (2015) identified a homozygous splice site mutation in the TCTN2 gene (613846.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. No patient material was available for further studies.
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]
Huppke, P., Wegener, E., Bohrer-Rabel, H., Bolz, H. J., Zoll, B., Gartner, J., Bergmann, C. Tectonic gene mutations in patients with Joubert syndrome. Europ. J. Hum. Genet. 23: 616-620, 2015. [PubMed: 25118024] [Full Text: https://doi.org/10.1038/ejhg.2014.160]
Sang, L., Miller, J. J., Corbit, K. C., Giles, R. H., Brauer, M. J., Otto, E. A., Baye, L. M., Wen, X., Scales, S. J., Kwong, M., Huntzicker, E. G., Stakianos, M. K., and 20 others. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145: 513-528, 2011. [PubMed: 21565611] [Full Text: https://doi.org/10.1016/j.cell.2011.04.019]