Joubert Syndrome 14

A number sign (#) is used with this entry because Joubert syndrome-14 (JBTS14) is caused by homozygous or compound heterozygous mutation in the TMEM237 gene (614423) on chromosome 2q33.

Description

Joubert syndrome-14 is an autosomal recessive developmental disorder characterized by severe mental retardation, hypoplasia of the cerebellar vermis and molar tooth sign (MTS) on brain imaging, hypotonia, abnormal breathing pattern in infancy, and dysmorphic facial features. Additional findings can include renal cysts, abnormal eye movements, and postaxial polydactyly (summary by Boycott et al., 2007 and Huang et al., 2011).

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

Clinical Features

Boycott et al. (2007) reported 10 patients with Joubert syndrome in a Canadian Hutterite population. Clinical features included severe to profound developmental delay, hypotonia, ataxia, abnormal breathing pattern, nystagmus, strabismus, and the molar tooth sign. The characteristic facial features included a tall forehead, malar flattening, hypertelorism, deep-set eyes, downslanting palpebral fissures, ptosis, epicanthal folds, arched eyebrows, high nasal bridge, short philtrum with tented upper lip, open mouth, and posteriorly rotated low-set ears. Other variable features included retinal colobomas, postaxial polydactyly, cystic kidneys, occipital encephalocele, and posterior fossa abnormalities. There was increased mortality. Seven of the patients had previously been diagnosed as having Meckel syndrome (see, e.g., 249000). Boycott et al. (2007) also reviewed a report of 3 Hutterite patients reported as having Meckel syndrome (Schurig et al., 1980) and concluded that all had a variant of Joubert syndrome. Mutations and deletions in the NPHP1 gene, as well as evaluation of known loci for Meckel and Joubert syndrome, were all excluded, suggesting further genetic heterogeneity.

Janecke et al. (2004) reported a consanguineous Austrian family in which 3 members had Joubert syndrome. The first affected infant showed an irregular breathing pattern soon after birth. She had aplasia of the cerebellar vermis, right-sided renal cyst, and poor psychomotor development with hypotonia. She died of pneumonia at age 4 years. A younger sib was noted to have meningocele, absence of the cerebellar vermis, and cystic kidneys on prenatal ultrasound, and the pregnancy was terminated. The third infant, born to another branch of this kindred, had abnormal breathing in the first weeks of life, irregular, jerky eye movements, aplasia of the cerebellar vermis, hypoplasia of the upper brainstem, and multiple renal cysts. She had poor psychomotor development and lack of speech. All 3 patients also had the morning glory sign on funduscopic examination, consisting of an enlarged, excavated disc with a central gliotic tuft and peripapillary pigment changes. CT showed funnel-shaped optic discs. None had any evidence of hepatic involvement. Linkage studies were inconclusive.

Inheritance

The transmission pattern of Joubert syndrome-14 in the families reported by Huang et al. (2011) was consistent with autosomal recessive inheritance.

Mapping

By genomewide homozygosity mapping in 4 Canadian Hutterite patients with JBTS, Huang et al. (2011) found linkage to a 7.5-Mb region on chromosome 2q33. Mapping studies in a consanguineous Austrian family with the disorder (Janecke et al., 2004) showed linkage to an overlapping region on 2q33.

Molecular Genetics

By homozygosity mapping followed by candidate gene analysis in 10 related Canadian Hutterite families with Joubert syndrome-14 (Boycott et al., 2007), Huang et al. (2011) identified a homozygous truncating mutation in the TMEM237 gene (R18X; 614423.0001). Homozygous or compound heterozygous mutations were also found in 3 additional families with the disorder (614423.0002-614423.0005), including the family reported by Janecke et al. (2004). All the mutations were predicted to result in a null allele. Protein extracts from patient cells showed perturbation of the noncanonical WNT (see 164820) pathway, with constitutive phosphorylation and hyperactivation of DVL1 (601365) and an increase in CTNNB1 (116806) levels.

Population Genetics

In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified the Joubert syndrome mutation R18X (rs199469707; 614423.0001) in heterozygous state in 122 individuals among 1,520 screened and in homozygous state in none, for a carrier frequency of 0.080 (1 in 12.5). This mutation is private to the Hutterite population.