Joubert Syndrome 26

A number sign (#) is used with this entry because of evidence that Joubert syndrome-26 (JBTS26) is caused by homozygous mutation in the KIAA0556 gene (616650) on chromosome 16p12.

Description

Joubert syndrome-26 is an autosomal recessive ciliopathy characterized by global developmental delay associated with cerebellar hypoplasia and variable additional abnormalities, including hypotonia and possibly pituitary abnormalities (summary by Sanders et al., 2015).

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

Clinical Features

Sanders et al. (2015) reported 3 children, born of consanguineous Saudi Arabian parents, with a mild form of Joubert syndrome. All had global developmental delay with variable hypotonia, transient tachypnea in the newborn period, and recurrent infections. One 8-year-old girl had mild dysmorphic features, including frontal bossing, ptosis, nystagmus, hypertelorism, and anteverted nares. A 2.5-year-old boy had cleft lip and palate and a small penis. Two patients, a girl and the boy, had panhypopituitarism with hypothyroidism and growth hormone deficiency. Brain imaging in all patients showed variable cerebellar hypoplasia, and the 2 patients with panhypopituitarism showed hypoplasia/aplasia of the anterior pituitary and an ectopic posterior pituitary. None had renal abnormalities.

Roosing et al. (2016) reported 2 brothers, born to first-cousin Indian parents, with Joubert syndrome. One brother presented at age 2 years with delayed motor and language development and mild ataxia. He showed mild hypotonia, oculomotor apraxia, nystagmus, and bilateral ptosis. ERG revealed cone dystrophy, but gross visual function was not impaired. At age 11, he could read and write with difficulty. His 2-year-old brother showed nystagmus and oculomotor apraxia with mild hypotonia and bilateral ptosis. He had a dysplastic left optic disc with slightly low amplitude of cone responses, but intact visual function. Brain imaging in both brothers demonstrated the characteristic molar tooth sign.

Inheritance

The transmission pattern of JBTS26 in the family reported by Sanders et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Saudi Arabian parents, with JBTS26, Sanders et al. (2015) identified a homozygous truncating mutation in the KIAA0556 gene (Q892X; 616650.0001). Patient cells showed near absence of the mutant transcript, consistent with nonsense-mediated mRNA decay and a complete loss of function. Patient-derived fibroblasts showed a significant reduction in the number of ciliated cells compared to controls, and the cilia that were present were abnormally long.

In 2 brothers, born of first-cousin Indian parents (family 1015), with JBTS26, Roosing et al. (2016) identified homozygosity for a frameshift mutation in the KIAA0556 gene (616650.0002), which segregated with the phenotype in the family.

Animal Model

Sanders et al. (2015) found that homozygous Kiaa0556-null mice showed a variable hydrocephalus phenotype with enlargement of the ventricles resulting from a block of cerebrospinal fluid flow in the cerebral aqueduct. However, detailed analysis showed no gross defects in ventricular ependymal cilium structure or motility. Disruption of the Kiaa0556 ortholog in C. elegans resulted in grossly normal ciliary structure, function, and transport, but ultrastructural analysis showed significant microtubule defects. Studies in C. elegans indicated that KIAA0556 interacts with an ARL13B (608922) ortholog to control cilium integrity.