Nephronophthisis 13

A number sign (#) is used with this entry because of evidence that nephronophthisis-13 (NPHP13) is caused by homozygous or compound heterozygous mutation in the WDR19 gene (608151) on chromosome 4p14.

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

Bredrup et al. (2011) studied a nonconsanguineous Moroccan family in which 3 of 6 sibs had nephronophthisis, 1 had mild proteinuria and a glomerular filtration rate at the lower limit of normal, and 2 sibs were unaffected. The oldest affected brother and sister had end-stage renal disease by 19 and 20 years of age, respectively, whereas their younger sister had end-stage renal failure at 13 years of age. The affected brother had no skeletal abnormalities, and ophthalmoscopy showed a retinal microaneurysm in the right eye. The younger of the 2 affected sisters had growth retardation, normal visual acuity and ophthalmoscopy, normal ultrasound of the thorax, and normal liver function.

Halbritter et al. (2013) reported 4 unrelated patients with nephronophthisis, all of whom had additional features of a ciliopathy, including retinal dystrophy (see Senior-Loken syndrome-8, 616307), dilatation of the intrahepatic bile ducts, and pancreatic and hepatic cysts. The findings broadened the spectrum of ciliary clinical features associated with WDR19 mutations.

Bredrup et al. (2011) performed haplotype analysis in a nonconsanguineous Moroccan family with nephronophthisis and found that the affected sibs shared 11 chromosomal regions, none of which encompassed known NPHP loci. Exome sequencing in 1 of the affected sibs revealed a single gene, WDR19 (608151), in which 2 variants segregated with disease in the family: the 3 sibs with NPHP and their younger sister with mild renal disease were all compound heterozygous for a missense (V345G; 608151.0004) and a nonsense (Y1023X; 608151.0005) mutation in WDR19. Their unaffected father was heterozygous for Y1023X and their 2 unaffected sibs were heterozygous for V345G; V345G was not found in 200 ethnically matched controls. However, their asymptomatic mother, who was born of consanguineous parents, was found to be homozygous for the V345G mutation. Based on bioinformatic analyses and the location of the mutation, Bredrup et al. (2011) proposed that the V345G variant only mildly affects IFT144 function, but that association with the nonsense mutation results in a renal phenotype.

Halbritter et al. (2013) identified biallelic mutations in the WDR19 gene in a patient with nephronophthisis who also exhibited dilatation of the intrahepatic bile ducts (608151.0008-608151.0009). The patient was ascertained from a larger cohort of 1,056 patients with nephronophthisis-related disorders who underwent genetic analysis.