Diagnosing Mendelian Kidney Disease: Hidden Niches in the (Kidney) Genome

A certain proportion of patients with Mendelian diseases are overlooked, although substantial technical advances in molecular genetics have been achieved. Massively parallel sequencing (MPS) increasingly identifies genetic variants of unknown significance, which may remain clinically unhelpful. Furthermore, difficult niches in the genome exist, which cannot be solved by standard MPS. In the reported family, autosomal dominant kidney disease leading to renal failure in middle adulthood runs through the maternal and paternal family. Comprehensive genetic analyses and customized functional evaluation solved the genetic etiologies: autosomal dominant polycystic kidney disease (ADPKD-PKD1, maternal) and autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD, paternal), with the index patient suffering from both diseases. The pathogenic variant in PKD1 (c.2180T>C, p.(Leu727Pro)) was not identified by exome sequencing but was unveiled by traditional long-range amplification protocols and whole genome sequencing. The ease of use of MPS increasingly tempts nonspecialized genetic laboratories to perform broad analyses of numerous diseases, which in specific cases may worsen the quality of investigations, ie, for the relatively frequent ADPKD.