title: 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.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Moumita
authors.initials: M
authors.lastname: Chaki
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefele
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Allen
authors.forename: Gokul
authors.initials: G
authors.lastname: Ramaswami
authors.forename: Sabine
authors.initials: S
authors.lastname: Janssen
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D003598:Cytoskeletal Proteins; D005190:Family; D056726:Genetic Association Studies; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000151:congenital* / Q000453:epidemiology / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human