Whole genome sequencing was performed in a family including two individuals affected by nephronophthisis.

Next-generation sequencing has revolutionized the molecular diagnosis of individuals affected by genetic kidney diseases. Indeed, rapid genetic testing in individuals with a suspected inherited nephropathy has not only important implications for diagnosis and prognosis but also for genetic counselling. Nephronophthisis (NPHP) and related syndromes, a leading cause of end-stage renal failure, are autosomal recessive disorders characterized by variable presentation and considerable locus heterogeneity with more than 90 genes described as single-gene causes. In this case report, we demonstrate the utility of whole genome sequencing (WGS) for the molecular diagnosis of NPHP by identifying two putative disease-causing intronic mutations in the NPHP3 gene including one deep intronic variant. We further show that both intronic variants, by affecting splicing, result in a truncated nephrocystin-3 protein. This study provides a framework for applying WGS as a first-line diagnostic tool for highly heterogeneous disease such as NPHP and further suggests that deep intronic variations are an important underestimated cause of monogenic disorders.