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 2 Egyptian sibs (A2556-21/22) with nephronophthisis and mutation in the WDR19 gene. Extrarenal manifestations included dilation of the intrahepatic bile ducts (Caroli disease). The authors stated that this was the first report of Caroli disease in WDR19-associated nephronophthisis, thus broadening the spectrum of ciliary features associated with WDR19 mutations.

Lee et al. (2015) reported 3 Korean sibs (I-1, I-2, and I-3) and an unrelated 1.5-year-old Korean boy (III-1) with nephronophthisis and mutation in the WDR19 gene. All 4 patients had chronic kidney disease of various stages at presentation, and 3 had progressed to end-stage renal disease. Kidney biopsies were performed in 2 patients (I-2 and I-3), which revealed chronic tubulointerstitial nephritis with diffuse global glomerulosclerosis involving 50 to 65% of glomeruli, as well as nonspecific immune complex deposits. Abdominal ultrasound showed bilateral small echogenic kidneys in the 3 sibs; prenatal ultrasound in the unrelated male infant showed bilateral large echogenic kidneys. In addition, all 4 patients had dilated intrahepatic bile ducts, and patient III-1 also showed pancreatic cysts.

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 2 Egyptian sibs (A2556-21/22) with nephronophthisis who also exhibited dilatation of the intrahepatic bile ducts (608151.0008-608151.0009). The proband was ascertained from a larger cohort of 1,056 patients with nephronophthisis-related disorders who underwent genetic analysis.

Lee et al. (2015) performed targeted exome sequencing covering 96 ciliopathy-related genes in 48 unrelated Korean pediatric patients with clinical suspicion of NPHP, and identified 2 probands with nephronophthisis who were compound heterozygous for missense mutations in the WDR19 gene: both carried the previously reported R1178Q variant (608151.0010) on 1 allele; the second mutation in a 21-year-old man (I-1) and his 2 affected sisters (I-2 and I-3) was E1235K (608151.0009), and in a 1.5-year-old boy (III-1) it was an L618P substitution (608151.0015). Sanger sequencing confirmed the mutations and their segregation with disease in both families, and none was detected in 100 Korean controls or in an in-house exome database of 80 Korean individuals. The authors also identified 2 Korean probands with NPHP and retinitis pigmentosa (Senior-Loken syndrome) and mutation in the WDR19 gene (SLSN8; 616307). Noting that all 6 patients showed intrahepatic bile duct dilation and some had hepatic fibrosis as well, the authors concluded that Caroli disease/syndrome might be a major extrarenal phenotype associated with mutations in the WDR19 gene.