Joubert Syndrome 10

A number sign (#) is used with this entry because Joubert syndrome-10 (JBTS10), which shows X-linked recessive inheritance, is caused by mutation in the OFD1 gene (300170).

Description

Joubert syndrome is characterized by a specific hindbrain formation, hypotonia, cerebellar ataxia, dysregulated breathing patterns, and developmental delay. Ciliary dysfunction is a key factor in the pathogenesis (Coene et al., 2009).

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

Clinical Features

Coene et al. (2009) reported a large kindred in which 8 males had severe to profound mental retardation and findings consistent with Joubert syndrome segregating in an X-linked recessive pattern. Three had died of recurrent infections. Five patients had postaxial polydactyly, and 3 had juvenile onset of retinitis pigmentosa. Investigation of 2 patients in detail showed delayed psychomotor development and dysmorphic features, including mild hirsutism, low-set ears, broad nasal bridge, prominent philtrum and maxillary arch, and full lips. One patient had irregular breathing patterns and poor feeding in infancy, and the other had recurrent infections. Brain MRI showed the molar tooth sign with hypoplasia of the cerebellar vermis and thickening of the superior cerebellar peduncles. Obligate female carriers were unaffected.

Field et al. (2012) reported 2 boys with Joubert syndrome-10 who were distantly related through the maternal line. Both boys had delayed motor development and were nonverbal, but had better receptive language and cognitive development. Both had macrocephaly and frontal bossing; one had downsloping palpebral fissures with epicanthal folds, and the other had deep-set eyes with infraorbital creases. One had severe cystic renal disease, whereas the other had increased echogenicity without renal impairment. Both had the molar tooth sign and an enlarged cisterna magna on brain MRI; only 1 had polymicrogyria, seizures, and EEG abnormalities. Neither had polydactyly or retinitis pigmentosa. Family history suggested that 2 deceased males may have been affected. Field et al. (2012) emphasized the relatively well-preserved nonverbal cognitive abilities of these boys.

In a comprehensive study of 279 patients from 232 unrelated families with Joubert syndrome in whom a genetic basis was determined by molecular analysis of 27 candidate genes, Bachmann-Gagescu et al. (2015) found a significant association between mutations in the OFD1 gene and encephalocele (odds ratio (OR) of 13.1).

Molecular Genetics

By linkage analysis followed by candidate gene sequencing of a family with X-linked recessive Joubert syndrome, Coene et al. (2009) identified a hemizygous 7-bp deletion in exon 21 of the OFD1 gene (300170.0008). A different truncating mutation in exon 21 (300170.0009) was found in an unrelated male with the disorder.

In 2 boys with Joubert syndrome-10 who were distantly related through the maternal line, Field et al. (2012) identified an 18-bp in-frame deletion in exon 8 of the OFD1 gene (300170.0010). Three unaffected females in the family, including both mothers, carried the mutation in heterozygous state. Field et al. (2012) noted that mutations proximal to exon 17 of the OFD1 gene are not necessarily associated with male lethality.