Chaki et al. (2012) reported a Saudi child, born of consanguineous parents, with a variant of nephronophthisis characterized by Leber congenital amaurosis and retinal degeneration resulting in blindness by age 2 years. Affected individuals in 3 additional families ... Chaki et al. (2012) reported a Saudi child, born of consanguineous parents, with a variant of nephronophthisis characterized by Leber congenital amaurosis and retinal degeneration resulting in blindness by age 2 years. Affected individuals in 3 additional families were later identified. In 1 family, 2 patients had NPHP at ages 8 and 9 years, respectively, and all had some degree of retinal degeneration, with 1 child being legally blind at age 5 months. One of the children also had seizures and developmental delay. In another family, a severely affected child had NPHP by age 8 years, retinal degeneration, flat electroretinogram, cerebellar vermis hypoplasia, facial dysmorphism, polydactyly, abnormal liver function tests, bronchiectasis, and obesity. Two patients in another family reportedly had liver failure.
In a Saudi child, born of consanguineous parents, with a variant of nephronophthisis-15, Chaki et al. (2012) identified a homozygous mutation in the CEP164 gene (614848.0001). The mutation was found by homozygosity mapping and whole-exome sequencing. Sequencing of ... In a Saudi child, born of consanguineous parents, with a variant of nephronophthisis-15, Chaki et al. (2012) identified a homozygous mutation in the CEP164 gene (614848.0001). The mutation was found by homozygosity mapping and whole-exome sequencing. Sequencing of the CEP164 gene in 856 patients with different NPHP-related ciliopathies identified homozygous or compound heterozygous mutations in the CEP164 gene in 3 additional families (614848.0002-614848.0005). Although the number of affected families was small, the findings supported a gradient of genotype/phenotype correlations in which null mutations can cause severe dysplastic phenotypes, whereas hypomorphic alleles cause milder degenerative phenotypes. Cellular studies showed that CEP164 is involved in the DNA repair response, suggesting that defects in the DNA repair response signaling pathway may contribute to the pathogenesis of NPHP and related ciliopathies. Chaki et al. (2012) suggested that loss of function of proteins that have a dual role in centrosome and DNA repair signaling could cause a disturbance of cell-cycle checkpoint controls, which is detrimental to progenitor cell survival both during embryogenesis and later during tissue maintenance.