Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Kidney Disease-Related Genes in Patients with Diabetic Kidney Disease

Abstract Diabetes is the most common cause of chronic kidney disease (CKD). For patients with diabetes and CKD, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes. Without histopathological confirmation, however, the underlying cause of their kidney disease is unclear. Recent studies have shown that next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease. Here, we set out to investigate the genetic basis of disease in non-diabetic kidney disease (NDKD) and diabetic kidney disease (DKD) patients by performing targeted NGS using a custom panel comprised of 345 kidney disease-related genes. Our analysis identified rare diagnostic variants that were consistent with the clinical diagnosis of 19% of the NDKD patients included in this study. Similarly, 22% of DKD patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel. Genetic variants suggestive of NDKD were detected in 3% of the diabetic patients included in this study. Our findings suggest that rare variants in kidney disease-related genes in the context of diabetic pathophysiology may play a role in the pathogenesis of kidney disease in patients with diabetes. Key MessagesWhat is already known about this subject? For patients with diabetes and chronic kidney disease, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes; without histopathological confirmation, however, the underlying cause of their kidney disease is unclear.Next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease.What are the new findings? Using targeted NGS and a custom panel comprised of 345 kidney disease-related genes, we found that 22% of diabetic kidney disease patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel.Genetic variants suggestive of non-diabetic kidney disease were detected in 3% of the diabetic patients included in this study.How might these results change the focus of research or clinical practice? Our findings suggest that rare variants in kidney disease-related genes in the context of diabetic pathophysiology may play a role in the pathogenesis of kidney disease in patients with diabetes.Importantly, improved understanding of the underlying disease process in diabetic kidney disease could have major implications in terms of patient care and monitoring as well as for research studies in this field.