ORPHA: 475; DO: 0111001;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q22.1 | Joubert syndrome 6 | 610688 | Autosomal recessive | 3 | TMEM67 | 609884 |
A number sign (#) is used with this entry because of evidence that Joubert syndrome-6 (JBTS6) is caused by homozygous or compound heterozygous mutation in the TMEM67 (609884) on chromosome 8q22.
Joubert syndrome is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities. Neuroradiologically, Joubert syndrome is characterized by peculiar malformation of the midbrain-hindbrain junction known as the 'molar tooth sign' (MTS) consisting of cerebellar vermis hypoplasia or aplasia, thick and maloriented superior cerebellar peduncles, and abnormally deep interpeduncular fossa (Romano et al., 2006).
For a general phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Baala et al. (2007) identified a genetically distinct form of Joubert syndrome, designated JBTS6. Two of the patients had been described by Romano et al. (2006). One, a 14-year-old girl, was severely handicapped and presented with hypotonia, severe mental retardation, stereotypic movements, and no independent walking. She had breathing abnormalities but no oculomotor apraxia or abnormal eye movements, and no renal or hepatic involvement. The other, a mildly affected 7-year-old girl, presented with hypotonia, ataxia, oculomotor apraxia, and abnormal eye movements. She had no breathing abnormalities or retinal, renal, or hepatic involvement. She had mild motor delay and moderate mental retardation. The third patient was a 7-year-old boy who presented with developmental delay, cerebellar ataxia, abnormal breathing, and vermis agenesis. No MRI was performed; the association of hyperechogenic kidneys with cysts and severe hepatic involvement with vermis agenesis led to the diagnosis of Joubert syndrome.
Otto et al. (2009) described 5 patients from 4 families with JBTS6. All 5 patients presented with ataxia, hypotonia or psychomotor retardation or showed cerebellar vermis hypo- or aplasia. All developed end-stage renal disease between 8 and 15 years of age, and 4 had hepatic fibrosis. Four had ocular involvement, including blindness, retinal degeneration or retinal coloboma.
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 TMEM67 gene and liver fibrosis (odds ratio (OR) of 17.3) and coloboma (OR of 22.9). In addition, there was a negative correlation between TMEM67 mutations and retinal disease (OR of 0.1).
The transmission pattern of Joubert syndrome-6 in the patients reported by Baala et al. (2007) was consistent with autosomal recessive inheritance.
Baala et al. (2007) found mutation in the TMEM67 gene (609884) in compound heterozygosity or homozygosity in patients with Joubert syndrome (609884.0006-609884.0010).
Otto et al. (2009) identified TMEM67 mutations (609884.0011; 609884.0013; 609884.0019; 609884.0021-609884.0023) in 4 (3.3%) of 120 unrelated probands with Joubert syndrome.
In a German girl with Joubert syndrome, Dafinger et al. (2011) identified 2 pathogenic missense mutations in the TMEM67 gene (I833T, 609884.0013 and P358L, 609884.0024), consistent with JBTS6, as well as a heterozygous 12-bp deletion in the KIF7 gene (611254.0008). The patient had impaired intellectual development, molar tooth sign on brain MRI, ataxia, hypertelorism, low-set ears, coloboma, and elevated liver enzymes.
Baala, L., Romano, S., Khaddour, R., Saunier, S., Smith, U. M., Audollent, S., Ozilou, C., Faivre, L., Laurent, N., Foliguet, B., Munnich, A., Lyonnet, S., and 9 others. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am. J. Hum. Genet. 80: 186-194, 2007. [PubMed: 17160906] [Full Text: https://doi.org/10.1086/510499]
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]
Dafinger, C., Liebau, M. C., Elsayed, S. M., Hellenbroich, Y., Boltshauser, E., Korenke, G. C., Fabretti, F., Janecke, A. R., Ebermann, I., Nurnberg, G., Nurnberg, P., Zentgraf, H., Koerber, F., Addicks, K., Elsobky, E., Benzing, T., Schermer, B., Bolz, H. J. Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics. J. Clin. Invest. 121: 2662-2667, 2011. [PubMed: 21633164] [Full Text: https://doi.org/10.1172/JCI43639]
Otto, E. A., Tory, K., Attanasio, M., Zhou, W., Chaki, M., Paruchuri, Y., Wise, E. L., Wolf, M. T. F., Utsch, B., Becker, C., Nurnberg, G., Nurnberg, P., Nayir, A., Saunier, S., Antignac, C., Hildebrandt, F. Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11). J. Med. Genet. 46: 663-670, 2009. [PubMed: 19508969] [Full Text: https://doi.org/10.1136/jmg.2009.066613]
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]