Importance of Copy Number Variant Analysis in Patients with Monogenic Kidney Diseases: Insights from 8 Years of Experience in an Expert Centre's Genome Diagnostic Laboratory

Background: Genetic testing can reveal monogenic causes of kidney diseases, offering diagnostic, therapeutic, and prognostic benefits. While single nucleotide variants (SNVs) and copy number variants (CNVs) can result in kidney disease, CNV analysis is not always included in genetic testing. With read depth-based tools for CNV detection (e.g. ExomeDepth) emerging, massively parallel sequencing can detect both SNVs and CNVs. This makes CNV detection more efficient as it does not require a separate test (e.g. SNP-array, MLPA). Methods: We investigated the diagnostic value of CNV analysis in 2,432 kidney disease patients genetically tested at the University Medical Centre Utrecht between 2014 and May 2022. We combined previous diagnostic testing results, encompassing SNVs and CNVs, with newly acquired results based on retrospective CNV analysis. The reported yield considers both ACMG variant classification and whether the genotype actually results in disease. Results: We report a diagnostic yield of at least 23% for our complete diagnostic cohort. The total diagnostic yield based solely on CNVs was 2.4%. The overall contribution of CNV analysis, defined as the proportion of positive genetic tests requiring CNV analysis, was 10.5% and varied among different disease subcategories, with the highest impact seen in congenital anomalies of the kidney and urinary tract and chronic kidney disease at a young age. We highlight the efficiency of exome-based CNV calling, which reduces the need for additional diagnostic tests. Furthermore, a complex structural variant, likely a COL4A4 founder variant, was identified. Additional findings unrelated to kidney diseases were reported in a small percentage of cases. This study also offers a comprehensive overview of our expert centre's diagnostic results over the past eight years covering both SNVs and CNVs. Conclusion: In summary, this study demonstrates the substantial diagnostic value of CNV analysis, providing insights into its contribution to the diagnostic yield and advocating for its routine inclusion in genetic testing of kidney disease patients.