Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies.

Background And Objectives: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes ( to ) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD.

Design, Setting, Participants, & Measurements: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years.

Results: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous deletion was, by far, the most frequent genetic defect (=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the group and 66% [61 of 92] for children without ). A homozygous deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non- group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood.

Conclusions: Mutations in genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.