Joubert Syndrome 5

A number sign (#) is used with this entry because of evidence that Joubert syndrome-5 (JBTS5) is caused by homozygous or compound heterozygous mutation in the gene encoding the centrosomal protein CEP290 (610142) on chromosome 12q21.

For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.

Clinical Features

Joubert syndrome (JBTS) is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities (Valente et al., 2006). Neuroradiologically, Joubert syndrome is characterized by a 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. A number of distinct syndromes sharing the MTS have been described, presenting wide phenotypic variability both within and among families (Gleeson et al., 2004).

Valente et al. (2006) described the JBTS5 phenotype as characterized mainly by the neurologic and neuroradiologic features of Joubert syndrome associated with severe retinal and renal involvement, but noted that the clinical spectrum was broad, including incomplete phenotypes such as cerebelloretinal and cerebellorenal syndromes. The full-blown JBTS5 phenotype largely overlaps that of Senior-Loken syndrome (SLSN; see 266900), which is characterized by retinitis pigmentosa plus juvenile nephronophthisis and is attributable to mutations in genes associated with nephronophthisis and encoding ciliary proteins.

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 CEP290 gene and retinal dystrophy (odds ratio (OR) of 22.9) and cystic kidney disease (OR of 3.3). None of 55 individuals with CEP290 mutations had seizures, suggesting a negative association with that feature.

Mapping

In Joubert syndrome, nephronophthisis (NPHP) is combined with retinal degeneration, cerebellar vermis aplasia, and mental retardation. Identification of 5 genes mutated in NPHP implicated primary cilia, basal bodies, and mechanisms of plantar cell polarity in the pathogenesis of renal cystic disease. In a worldwide cohort including 90 individuals with JBTS, recessive mutations in known NPHP-associated genes were found in only 1% of JBTS cases (Utsch et al., 2006). To identify further causative genes for NPHP, Sayer et al. (2006) performed a whole-genome search for linkage by homozygosity mapping in 25 consanguineous kindreds with NPHP, SLSN, or JBTS, ascertained worldwide, each of which had 2 affected individuals and was negative for mutations in known NPHP genes. Three kindreds showed an overlap of nonparametric lod score (NPL) peaks on 12q indicating potential homozygosity by descent. Refinement of the linkage narrowed the region to 12q21.32-q21.33.

Valente et al. (2006) identified the JBTS5 locus on 12q21.31-q21.33 in linkage analysis from consanguineous families with Joubert syndrome-related disorders (JSRDs), which showed the neurologic features of Joubert syndrome associated with multiorgan involvement (mainly retinal dystrophy and nephronophthisis).

Identification of causative mutations in the CEP290 gene in families with JBTS5 localized the phenotype to 12q21.32 (Sayer et al., 2006; Valente et al., 2006).

Molecular Genetics

Upon mutation analysis within the NPHP6 genetic interval, Sayer et al. (2006) identified an identical homozygous nonsense mutation, 5668G-T (G1890X), located in the CEP290 gene (610142.0001), which had been described as a component of the centrosomal proteome (Andersen et al., 2003), in 2 kindreds. Further mutation screening in 96 unrelated individuals with JBTS by direct sequencing identified this mutation in a third family. Altogether Sayer et al. (2006) identified 8 distinct mutations in CEP290 in 7 JBTS families.

In 5 families with JBTS, Valente et al. (2006) found 5 mutations in the CEP290 gene, including 3 nonsense mutations resulting in premature protein truncation, one 1-bp deletion generating a frameshift and a premature stop codon, and 1 missense mutation (W7C; 610142.0003).