Diagnostic Utility of Exome Sequencing for Polycystic Kidney Disease

ImportanceMost studies of ADPKD genetics have used select cohorts, focusing on PKD1 and PKD2 and more recently several other cystic genes. However, the population prevalence of ADPKD and the contribution of each cystic gene to ADPKD are not well understood. ObjectiveDetermine the prevalence of ADPKD, contribution of PKD1, PKD2, and other cystic genes to ADPKD in a large, unselected cohort. Design, Setting, and ParticipantsWe determined the prevalence of ADPKD In an unselected health system-based cohort of 173,954 subjects with the existing exome sequencing and extensive electronic health records, including abdominal imaging. The presence of genetic variants in PKD1, PKD2, and eleven other cystic genes was evaluated. Rare genetic variants were identified in patients with chart review confirmed diagnosis of ADPKD. Main OutcomesDiagnosis of ADPKD and presences of rare (AF<0.0001) missense, protein-truncating variants (PTVs), or copy number variants deletions (CNV) in PKD1, PKD2, or PTVs and CNVs in the following 11 genes: ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, LRP5, PKHD1, PRKCSH, SEC61B, and SEC63. ResultsAmong 173,954 patients, there were 235 patients with chart review confirmed ADPKD (0.135%). Among patients with PTV or CNV in PKD1, 66/70 (94.2%) had ADPKD and 43/44 (97.7%) of patients with PTV or CNV in PKD2 had ADPKD. In contrast, only 24/77 (31.2%) patients with a PKD1 missense variant previously classified as "likely pathogenic" had ADPKD. A rare variant was identified in a cystic gene in 180/235 (76.6%) of ADPKD patients, with the most common genes implicated PKD1 (127) and PKD2 (34) and then IFT140 (7), PKHD1 (3), GANAB (4), HNF1B (2), ALG8 (1), ALG9 (1), IFT140+PKHD1 (1). The yield for a genetic determinant of ADPKD was 91.3% among those with a family history compared to 50.6% among those without a family history (p<0.0001). We report several previously unreported variants where pedigree data suggest pathogenicity. Atypical cystic genes ALG8, ALG9, GANAB, HNF1B, IFT140, and SEC63 were associated with having any kidney or liver cystic ICD code, but not diagnosed ADPKD. ConclusionsExome sequencing established the molecular diagnosis for the vast majority of patients with ADPKD, revealed a wider range of ADPKD with atypical cystic genes. Additional population-based research cohorts are needed to carefully curate missense PKD1 variants and variants in atypical cystic genes.