Clinical Spectrum of Disease in Patients with Large Homozygous NPHP1 Gene Deletions

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Background: Nephronophthisis (NPHP) is a rare, inherited ciliopathy, leading to progressive fibrosis and cyst formation at the corticomedullary junction of the kidney leading to kidney failure typically in childhood. Extra renal manifestations such as retinitis pigmentosa and brain malformations may also occur. The most frequent genetic cause of NPHP are large homozygous deletions affecting NPHP1, accounting for approximately 25% of cases. In this study, we report a large cohort of patients with NPHP1 large gene deletions and test the hypothesis whether the presence of large deletions correlates with early or late onset kidney failure / extra renal manifestations. Methods: We reviewed a large worldwide multiethnic cohort of patients with NPHP1 whole gene deletions collected over the last 4 decades. We identified a cohort of 372 patients who had a molecular genetic diagnosis of a large homozygous NPHP1 gene deletion (multi-exon or whole gene). Molecular diagnostics were performed using a combination of MLPA assays and quantitative multiplex polymerase chain reaction to detect large homozygous NPHP1 deletions. Clinical data was available for 353 cases. We assessed age of kidney failure (CKD stage 5) as well as the presence of extra renal manifestations (retinitis pigmentosa and features of Joubert syndrome) and if there was known consanguinity. Results: Of the cohort of 353 patients, with clinical data available, the rate of known consanguinity was 16%. We identified 154 patients who had reached kidney failure. Early kidney failure, defined as 8 years of age or earlier occurred in 20 patients (5.6%), whereas late kidney failure (>20 years of age) occurred in 11 patients (7%). The median age of kidney failure was 12 years of age. Isolated NPHP was seen in the majority of cases (91%). There was no significant difference in rates of extra renal manifestations between early and late onset kidney failure. Conclusion: Homozygous large NPHP1 gene deletions can present as early onset NPHP (< 8 years) but also may be found in adult patients with kidney failure. This study helps to increase the diagnostic awareness of how the NPHP1 deletion related kidney disease may present in its extremes and provides a valuable cohort to look for genetic kidney disease modifiers.

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