Nephronophthisis 14

A number sign (#) is used with this entry because nephronophthisis-14 (NPHP14) is caused by homozygous mutation in the ZNF423 gene (604557) on chromosome 16. Heterozygous mutation in the ZNF423 gene causes Joubert syndrome-19 (JBTS19).

For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100).

For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).

Clinical Features

Chaki et al. (2012) reported 2 Turkish sibs, born of consanguineous parents (family F824), with infantile-onset NPHP, cerebellar vermis hypoplasia, and situs inversus. Chaki et al. (2012) referred to these patients as having an NPHP-related ciliopathy, despite the presence of cerebellar vermis hypoplasia. Chaki et al. (2012) also reported 2 unrelated patients with Joubert syndrome. One patient had cerebellar vermis hypoplasia, Leber congenital amaurosis (see 204000), and polycystic kidney disease. The other patient had polycystic kidney disease, nephronophthisis, retinal degeneration, cerebellar vermis hypoplasia, and perinatal breathing abnormalities. Neither of the Joubert patients had a family history of a similar disorder.

Inheritance

The transmission pattern of NPHP14 in the family reported by Chaki et al. (2012) was consistent with autosomal recessive inheritance. Two patients with Joubert syndrome-19 were found to carry heterozygous ZNF423 mutations, suggesting autosomal dominant inheritance.

Molecular Genetics

By homozygosity mapping and whole-exome sequencing of 2 Turkish sibs with nephronophthisis, Chaki et al. (2012) identified a homozygous mutation in the ZNF423 gene (P913L; 604557.0001). The mutation was predicted to result in a loss of function. Two of 96 additional patients with Joubert syndrome were found to carry heterozygous ZNF423 mutations (604557.0002 and 604557.0003). The heterozygous mutations caused a dominant-negative effect on protein function in cellular studies.