Elucidating the Molecular Landscape of Cystic Kidney Disease: Old Friends, New Friends and Some Surprises

ABSTRACT Cystic kidney diseases (CyKD) are a diverse group of disorders affecting more than 1 in 1000 individuals. Over 120 genes are implicated, primarily encoding components of the primary cilium, transcription factors, and morphogens. Prognosis varies greatly by molecular diagnosis. Causal variants are not identified in 10%–60% of individuals due to our limited understanding of CyKD. To elucidate the molecular landscape of CyKD, we queried the CAG Biobank using the ICD10 codes N28.1, Q61.1, Q61.11, Q61.19, Q61.2, Q61.3, and Q61.8 to identify individuals with CyKD. One hundred eight individuals met clinical criteria for CyKD and underwent proband‐only exome sequencing. Causal variants were identified in 86/108 (80%) individuals. The most common molecular diagnoses were PKD1 ‐related autosomal dominant polycystic kidney disease (32/108; 30%) and autosomal recessive polycystic kidney disease (21/108; 19%). Other common molecular diagnoses were ciliopathy syndromes (7/108; 6.5%) and Tuberous Sclerosis (6/108; 5.6%). Seven individuals had variants in genes not previously associated with CyKD (7/108; 6.5%). Candidate genes were identified in five individuals (5/108; 4.5%). Discordance between molecular and clinical diagnosis was present in two individuals. We demonstrate a high molecular diagnosis rate in individuals with CyKD that can result in diagnostic reclassification, supporting a role for genetic testing in CyKD.