A number sign (#) is used with this entry because of evidence that Joubert syndrome-32 (JBTS32) is caused by homozygous mutation in the SUFU gene (607035) on chromosome 10q24.

Joubert syndrome-32 (JBTS32) is an autosomal recessive developmental disorder characterized by delayed psychomotor development, intellectual disability, dysmorphic facial features, and postaxial polydactyly. Brain imaging shows cerebellar abnormalities consistent with the molar tooth sign (MTS) (summary by De Mori et al., 2017).

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

De Mori et al. (2017) reported 4 children from 2 unrelated consanguineous families with developmental delay, intellectual disability, and additional neurologic features associated with cerebellar abnormalities. The families were of Italian (family COR369) and Egyptian (family MTI-2023) descent. Brain imaging showed mild cerebellar vermis hypoplasia with elongated superior cerebellar peduncles and a deepened interpeduncular fossa, indicative of the molar tooth sign. The Italian sibs also had polymicrogyria on brain imaging. The patients had similar dysmorphic features, including hypertelorism, broad and depressed nasal bridge, and frontal bossing. One patient from each family had macrocephaly and global macrosomia, and 1 sib from the Italian family had tall stature. Additional features included oculomotor apraxia, ataxia, dysarthria, and nystagmus (in the Egyptian sibs). Three patients had postaxial polydactyly. None had overt seizures, but 1 patient had an abnormal EEG.

The transmission pattern of JBTS32 in the families reported by De Mori et al. (2017) was consistent with autosomal recessive inheritance.

In 4 children from 2 unrelated consanguineous families with Joubert JBTS32, De Mori et al. (2017) identified 2 different homozygous missense mutations in the SUFU gene (I406T, 607035.0008 and H176R, 607035.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional cellular expression studies showed that both variants were hypomorphic, causing significantly reduced SUFU stability, decreased binding to GLI3 (165240), and decreased production of the repressor GLI3R (see 165240). Patient cells showed altered expression levels of several SHH (600725) target genes, including significant overexpression of BCL2 (151430), GLI1 (165220), and PTCH1 (601309), indicating that the mutations impaired SUFU-mediated repression of the SHH pathway. De Mori et al. (2017) concluded that germline mutations in the SUFU gene can cause deregulation of SHH signaling, resulting in recessive developmental defects of the central nervous system and limbs that share features of both SHH-related disorders and ciliopathies.