An NGS-based investigation of copy number variants in the diagnosis and severity of adult polycystic kidney disease.

Polycystic kidney disease (PKD) is a Mendelian renal disease characterised by the development of cysts and progressive decline in kidney function, leading to kidney failure. Although genetic testing can provide a precise molecular diagnosis of PKD in the majority of cases, 6-13% of patients remain unsolved. Copy number variants (CNVs) are an established pathogenic mechanism in PKD, however detection typically relies on multiplex ligation-dependent probe amplification (MLPA) which is resource intensive and separate to next-generation sequencing (NGS) pipelines. Here, a bioinformatics tool ClinCNV was used to call CNVs from NGS data of 371 people with PKD who had previously undergone short nucleotide variant (SNV) analysis with a standard NGS pipeline. Diagnostic CNVs were confirmed in 13 patients across 7 families, increasing the diagnostic yield from 86.5 to 90.0%. We also tested CNVs as potential disease modifiers. Regression models indicated an association of cystic gene duplication burden to worse kidney survival (HR = 1.56, 95% CI: 1.26, 1.93, adj-p = 0.0004). These models also revealed that duplication burden in genes unrelated to cystic kidney disease associated with the absence of liver cysts, possibly driven by a region containing LRP5L. These results demonstrate the utility of targeted gene panel and exome sequencing for the detection of CNVs in key PKD genes.