ORPHA: 475; DO: 0111003;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q11.1-q11.2 | Joubert syndrome 8 | 612291 | Autosomal recessive | 3 | ARL13B | 608922 |
A number sign (#) is used with this entry because of evidence that Joubert syndrome-8 (JBTS8) is caused by homozygous or compound heterozygous mutation in the ARL13B gene (608922) on chromosome 3q11.
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Cantagrel et al. (2008) studied 2 families with Joubert syndrome in which novel mutations in the ARL13B gene were subsequently found. The phenotype consisted predominantly of classical Joubert syndrome, with all patients displaying the molar tooth sign. In the Pakistani pedigree in which the disorder was mapped, 2 of the 3 affected individuals had a small occipital encephalocele. In the other family, from the United States, there was no occipital encephalocele, and there were no other supratentorial cerebral abnormalities. Diagnostic ultrasound, performed on both families, found no renal abnormalities. The possibility that renal symptoms could develop in the affected individuals was considered, as studies of urinary concentration defects, a more sensitive measure of early kidney involvement, were not available from any of the patients.
Thomas et al. (2015) reported a boy, born of consanguineous Tunisian parents, with Joubert syndrome. He was noted to have abnormal eye movements since birth. At age 1 month, he had jaundice, hepatomegaly, hyperventilation, hypertonia, and absence of eye contact. Later in early childhood, the liver abnormalities had disappeared, but he showed delayed psychomotor development with absent speech, pale optic discs, absent electroretinogram, ataxic gait, and the molar tooth sign on brain imaging. He was also obese.
Using linkage analysis in a consanguineous Pakistani family, Cantagrel et al. (2008) assigned the JBTS8 interval to a 107- to 112-cM region on chromosome 3p12.3-q12.3.
The transmission pattern of Joubert syndrome-8 in the families reported by Cantagrel et al. (2008) was consistent with autosomal recessive inheritance.
The JBTS8 interval defined by Cantagrel et al. (2008) contained 41 genes, of which 4 were considered strong candidates based on their identification within the cilia proteome. In the Pakistani family in which linkage to 3p12.3-q12.3 was established, Cantagrel et al. (2008) identified a homozygous missense mutation in exon 3 of the ARL13B gene (R79Q; 608922.0001). The affected individual from another family was compound heterozygous for a nonsense mutation (W82X; 608922.0002) and a missense mutation (R200C; 608922.0003). Overexpression of human wildtype, but not patient mutant, ARL13B rescued the Arl13b 'scorpion' zebrafish mutant, demonstrating that ARL13B has an evolutionarily conserved role in mediating cilia function in multiple organs.
In a boy, born of consanguineous Tunisian parents, with JBTS8, Thomas et al. (2015) identified a homozygous missense mutation in the ARL13B gene (Y86C; 608922.0004). The mutation was found by a combination of homozygosity mapping and candidate gene sequencing. Expression of the mutation in arl13b-null zebrafish and mouse embryonic fibroblasts null for Arl13b showed only partial rescue of the null phenotype, consistent with a hypomorphic allele. Thomas et al. (2015) found expression of the ARL13B gene within cilia in ventromedial hypothalamic neurons, and noted that the patient also had obesity. The patient had previously been reported as patient 3 by Romano et al. (2006).
Cantagrel, V., Silhavy, J. L., Bielas, S. L., Swistun, D., Marsh, S. E., Bertrand, J. Y., Audollent, S., Attie-Bitach, T., Holden, K. R., Dobyns, W. B., Traver, D., Al-Gazali, L., and 14 others. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am. J. Hum. Genet. 83: 170-179, 2008. [PubMed: 18674751] [Full Text: https://doi.org/10.1016/j.ajhg.2008.06.023]
Romano, S., Boddaert, N., Desguerre, I., Hubert, L., Salomon, R., Seidenwurm, D., Bahi-Buisson, N., Nabbout, R., Sonigo, P., Lyonnet, S., Brunelle, F., Munnich, A., de Lonlay, P. Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study. Neuropediatrics 37: 42-45, 2006. [PubMed: 16541367] [Full Text: https://doi.org/10.1055/s-2006-923838]
Thomas, S., Cantagrel, V., Mariani, L., Serre, V., Lee, J.-E., Elkhartoufi, N., de Lonlay, P., Desguerre, I., Munnich, A., Boddaert, N., Lyonnet, S., Vekemans, M., Lisgo, S. N., Caspary, T., Gleeson, J., Attie-Bitach, T. Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity. Europ. J. Hum. Genet. 23: 621-627, 2015. [PubMed: 25138100] [Full Text: https://doi.org/10.1038/ejhg.2014.156]