A number sign (#) is used with this entry because Joubert syndrome-21 (JBTS21) is caused by homozygous or compound heterozygous mutation in the CSPP1 gene (611654) on chromosome 8q13.

Joubert syndrome is an autosomal recessive congenital condition characterized by a unique brainstem and cerebellar malformation comprising cerebellar vermis hypoplasia and/or dysplasia, elongated superior cerebellar peduncles, and deepened interpeduncular fossa, which together are recognized as the 'molar tooth sign' on brain MRI. The most common clinical features include delayed psychomotor development, hypotonia, abnormal respiratory patterns in the neonatal period, oculomotor apraxia, and cerebellar ataxia. Additional features may include retinal degeneration, cystic kidney, liver fibrosis, and polydactyly. It is caused by ciliary defects and is part of a spectrum of disorders known as 'ciliopathies' (summary by Akizu et al., 2014).

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

Tuz et al. (2014) reported 19 individuals with Joubert syndrome-21; detailed clinical information was available for 18 patients from 14 families. All patients had cerebellar vermis hypoplasia with the molar tooth sign on brain MRI. Phenotypic severity ranged from severely affected individuals with profound developmental delay to those with milder developmental disabilities. Most patients had ptosis, and about half had nystagmus or oculomotor apraxia. Rare features included occipital encephalocele (1 patient), echogenic kidneys (1 patient), retinal changes (2 patients), liver dysfunction (2 sibs), and seizures (1 patient). Four patients had features consistent with Jeune asphyxiating thoracic dystrophy (see SRTD1, 208500), including short ribs, bell-shaped chest, and pulmonary hypoplasia. All 4 had apnea or tachypnea. Other abnormal brain MRI findings found in some patients included superior cerebellar hypoplasia, enlarged ventricles, a posterior gap in the foramen magnum, heterotopia, and polymicrogyria.

Shaheen et al. (2014) reported 3 patients from 2 consanguineous Canadian Schmiedeleut Hutterite families with classic clinical and radiologic features of Joubert syndrome, including the molar tooth sign on brain imaging. In 1 family, a 7-year-old girl had global developmental delay, hypotonia, ataxia, and strabismus. Two sibs from the second family had a more severe phenotype resulting in death in infancy. Brain imaging of these patients showed hypoplastic inferior cerebellar vermis, dysplastic superior cerebellar vermis, communication between a posterior fossa cyst and fourth ventricle, thickened horizontal superior cerebellar peduncles, and reduced anteroposterior dimension of the mesencephalon; 1 patient had a Dandy-Walker malformation apparent antenatally. Shaheen et al. (2014) also reported 2 fetuses in a consanguineous family of Saudi Arabian origin who were stillborn with severe brain malformations reminiscent of Meckel syndrome (249000). Features included hydranencephaly, large fontanels and wide cranial sutures, occipital encephalocele, anophthalmia/partially fused eyes, single nostril, and hyperechogenic kidneys. Another pregnancy in this family ended in a spontaneous first-trimester abortion.

Akizu et al. (2014) reported 6 unrelated patients with classic features of Joubert syndrome. The children had hypotonia, developmental delay, intellectual disability, apneic episodes in the neonatal period, and the molar tooth sign on brain imaging. Half of the affected children also had variable ophthalmologic findings, such as retinopathy, oculomotor apraxia, nystagmus, and ptosis. Three had hypoplasia of the corpus callosum and the brainstem, and 2 had sensorineural hearing loss. Hepatic fibrosis, nephronophthisis, and polydactyly were not present. The patients were of various ethnic origins, including Mexican, Indian, Chinese, Libyan, and Egyptian, and were ascertained from a larger cohort of 287 probands.

The transmission pattern of JBTS21 in the families reported by Tuz et al. (2014), Shaheen et al. (2014), and Akizu et al. (2014) was consistent with autosomal recessive inheritance.

In 19 patients from 15 families with Joubert syndrome, Tuz et al. (2014) identified biallelic truncating mutations in the CSPP1 gene (see, e.g., 611654.0001-611654.0007). When samples were available, Sanger sequencing confirmed that the variants segregated in the families. There were no apparent genotype/phenotype correlations. Fibroblasts from 2 unrelated patients showed absence of CSPP1 immunostaining in the axoneme, although the signal at the base of the cilium remained. Patient cells showed defects in ciliogenesis, with decreased numbers of cilia, decreased ciliary length, and evidence of decreased trafficking of the ciliary proteins ARL13B (608922) and ADCY3 (600291) to the axoneme compared to controls. Collectively, the results suggested a loss of function.

In 3 patients from 2 consanguineous Canadian Hutterite families with JBTS21, Shaheen et al. (2014) identified a homozygous truncating mutation in the CSPP1 gene (611654.0008). Two fetuses from a consanguineous Saudi family with a more severe phenotype reminiscent of Meckel syndrome were found to carry a different homozygous truncating mutation (611654.0009). A patient skin sample showed decreased numbers of ciliated fibroblasts, with complete loss of the ciliary localization of RPGRIP1L (610937) compared to controls. These cells also showed markedly impaired SHH (600725) signaling, indicating that the ciliogenesis defect has downstream consequences. Analysis of the cell cycle showed no difference between patient cells and control cells.

In 6 unrelated patients with Joubert syndrome, Akizu et al. (2014) identified biallelic truncating or splice site mutations in the CSPP1 gene (see, e.g., 611654.0010-611654.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. The patients were ascertained from a larger cohort of 287 probands with Joubert syndrome who underwent whole-exome sequencing. Fibroblasts from 1 patient showed absence of the CSPP1 protein, but normal cell proliferation. Serum-starved patient cells showed defective ciliogenesis, with decreased levels of ARL13B, although the number of centrosomes was normal. Akizu et al. (2014) concluded that CSPP1 is involved in neural-specific functions of primary cilia.

Tuz et al. (2014) found that morpholino knockdown of the cspp1a gene in zebrafish embryos resulted in a curved body shape, dilated ventricles, and pronephric cysts, consistent with a ciliopathy. The neurocranium also showed patterning defects. The presence of cilia did not appear to be altered in zebrafish mutants, but there was reduced ciliary localization of arl13b.