The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Kidney Int. 2023 Aug;104(2):378-387. doi: 10.1016/j.kint.2023.05.007. Epub 2023 May 23.


Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Keywords: ciliopathy; cilium; end-stage kidney disease; nephronophthisis; tubulointerstitial nephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Ciliopathies* / genetics
  • Humans
  • Kidney Diseases, Cystic* / genetics
  • Kidney Diseases, Cystic* / pathology
  • Kidney Failure, Chronic* / diagnosis
  • Mutation
  • Polycystic Kidney Diseases* / complications

Supplementary concepts

  • Nephronophthisis, familial juvenile