Joubert Syndrome 33

A number sign (#) is used with this entry because of evidence that Joubert syndrome-33 (JBTS33) is caused by homozygous or compound heterozygous mutation in the PIBF1 gene (607532) on chromosome 13q21.

Description

Joubert syndrome represents a classic ciliopathy characterized by hypotonia, ataxia, cognitive impairment, and a distinctive brain malformation, the 'molar tooth sign.' In addition, retinal dystrophy, cystic kidney disease, liver fibrosis, and polydactyly occur in a subset of patients (summary by Wheway et al., 2015).

For a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).

Clinical Features

Wheway et al. (2015) reported 6 children with Joubert syndrome from 4 Hutterite families, designated H1 to H4. The 5 patients for whom clinical information was available showed mild to moderate developmental delay, and 4 also exhibited ataxia. Brain MRI was performed in 5 patients, of whom 3 exhibited the molar tooth sign and 2 did not. Other features seen on MRI included mild to moderate vermian hypoplasia, dysplasia of superior cerebellum, thickening of superior cerebellar peduncles, and deep interpeduncular fossa.

Molecular Genetics

By whole-exome sequencing in 2 brothers with Joubert syndrome from a family of Schmiedeleut Hutterite descent (family H1), who were negative for mutations in known JBTS-associated genes, Wheway et al. (2015) identified homozygosity for a missense mutation in the PIBF1 gene (D637A; 607532.0001) for which their parents were heterozygous. Homozygosity for the D637A mutation was also detected in 3 affected children from 2 more Hutterite families (H2 and H3), suggesting a founder effect. In a fourth Hutterite family (H4), the unaffected parents and an unaffected child were heterozygous for D637A; mutation status was not reported for the proband, who died at 15 days of life. Analysis of an additional 643 Joubert families negative for mutation in known JBTS-associated genes identified 2 in which affected individuals were compound heterozygous for mutations in the PIBF1 gene: in both families, 1 of the mutations was an R405Q substitution (607532.0002), whereas the second mutation was a different truncating mutation in each family (see, e.g., 607532.0003).