Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies

Abstract

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in the first three decades of life. Mutations in 13 genes (NPHP1-NPHP11, AHI1, and CC2D2A) cause NPHP with ubiquitous expression of the corresponding proteins consistent with the multiorgan involvement of NPHP-related diseases. The genotype-phenotype correlation in these ciliopathies can be explained by gene locus heterogeneity, allelism, and the impact of modifier genes. In some NPHP-related ciliopathies, the nature of the recessive mutations determines disease severity. In order to define the genotype-phenotype correlation more clearly, we evaluated a worldwide cohort of 440 patients from 365 families with NPHP-related ciliopathies, in whom both disease-causing alleles were identified. The phenotypes were ranked in the order of severity from degenerative to degenerative/dysplastic to dysplastic. A genotype of two null alleles caused a range of phenotypes, with an increasing order of severity of NPHP1, NPHP3, NPHP4, NPHP5, NPHP2, NPHP10, NPHP6, to AHI1. Only NPHP6 showed allelic influences on the phenotypes; the presence of two null mutations caused dysplastic phenotypes, whereas at least one missense allele rescued it to a milder degenerative phenotype. We also found nine novel mutations in the NPHP genes. Thus, our studies have important implications for genetic counseling and planning of renal replacement therapy.

Figure 1. Representative images of degenerative and dysplastic clinical features observed in nephronophthisis (NPHP)-related ciliopathies

(a) Renal ultrasound from an individual with (degenerative) NPHP. Cysts occur only at the corticomedullary junction and are marked with arrowheads. (b) Renal ultrasound from an individual with (dysplastic) Meckel–Gruber syndrome (MKS, A1633-22). Cysts occur throughout an enlarged kidney and are marked with arrowheads. (c) Autopsy kidney specimen from a fetus with MKS showing bilateral enlarged kidneys interspersed with small, pinhead-sized cysts. (d) Renal histology showing cystic dysplastic kidneys with marked interstitial fibrosis in MKS. (e) Ophthalmoscopy reveals retinitis pigmentosa in the right eye of a patient with (degenerative) Senior–Løken syndrome. (f) Left eye of an NPHP patient with diffuse retinal atrophy with markedly pale discs and enlarged cup. (g) Liver histology showing dysgenesis of the hepatic portal triad with hyperplastic biliary ducts and congenital hepatic fibrosis. (h) Brain magnetic resonance imaging with ‘molar tooth sign’ (marked with a circle) demonstrating vermis hypoplasia, a dysplastic phenotype observed in a JBTS patient. (i) Chest X-ray image of a patient showing situs inversus. (j) Postaxial hexadactyly in an MKS fetus.

Figure 2

Flowchart for a suggested genotyping strategy in nephronophthisis (NPHP)-related ciliopathies (Meckel–Gruber syndrome patients are excluded). ESRD, end-stage renal disease.