# Results of Multigene Panel Testing, Including PKD1, in >1,200 Patients With Cystic Kidney Disease: A Retrospective Analysis

## TL;DR

This study shows that genetic testing in over 1,200 patients with cystic kidney disease identified a genetic cause in nearly half of the cases, highlighting the importance of multigene panel testing for accurate diagnosis.

## Contribution

The study provides empirical data on the diagnostic yield of multigene panel testing for cystic kidney disease in a real-world clinical setting.

## Key findings

- A genetic cause was identified in 49.4% of patients with cystic kidney disease.
- Variants in PKD1 accounted for 65.6% of positive results, emphasizing its clinical significance.
- Copy number variants made up 9.5% of positive results, with many small deletions detected.

## Abstract

Mounting evidence supports that identifying the specific molecular etiology for individuals with cystic kidney disease (CyKD) is important for prognostication, surveillance, identifying related living donors, and defining familial risk, even in cases in which a clinical diagnosis appears straightforward. In this study, we aimed to investigate the yield of genetic findings and the unique variant characteristics using multigene panel testing (MGPT) in a referral laboratory setting for an unselected population of patients with an indication of CyKD.

Cross-sectional study.

A retrospective analysis of 1,235 genetic testing reports from patients with suspected CyKD who pursued MGPT was performed.

A positive result in a gene associated with CyKD was identified in 49.4% (610/1235) of patient reports, identifying 468 unique variants classified as pathogenic or likely pathogenic in 20 unique genes. Variants in PKD1, a gene complicated by homology to 6 different pseudogenes, contributed to 65.6% (400/610) of positive results. Copy number variants (CNVs) were identified in 9.5% (58/610) of positive results, with 30.4% (17/56) of deletions consisting of 4 exons or less. Variants of uncertain significance that were suspicious for being pathogenic (susVUS) were identified in 57.0% (94/165) of patients with inconclusive results.

Genetic analysis was targeted to the genes included on the panel at the time of testing. As new evidence emerges supporting additional gene-disease associations, there is potential for additional positive results.

Thoughtful selection of carefully curated MGPT optimized to detect technically challenging variants can identify the molecular etiology in individuals presenting with CyKD. Further investigation of susVUS through segregation analysis in families may contribute to additional positive results.

Data informing the yield of multigene panel testing (MGPT) for individuals with cystic kidney disease (CyKD) is increasing. In this study, we retrospectively reviewed MGPT results from 1,235 individuals with suspected CyKD. A positive result in one of 20 CyKD-associated genes, including PKD1, was identified in 49.4% (610/1235) of patient reports. Copy number variants (CNVs) accounted for 9.5% (58/610) of positive results, with 30.4% (17/56) of deletions consisting of 4 exons or less. Suspicious variants of uncertain significance were identified in 57.0% (94/165) of patients with inconclusive results. MGPT can identify the molecular etiology of CyKD and, prior to ordering, should be carefully evaluated for relevant gene content, capabilities for technically challenging genes like PKD1, sensitivity to detect CNVs, and reporting policy for variants of uncertain significance.