Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology

Abstract

Advances in next-generation sequencing (NGS) techniques, including whole exome sequencing, have facilitated cost-effective sequencing of large regions of the genome, enabling the implementation of NGS in clinical practice. Chronic kidney disease (CKD) is a major contributor to global burden of disease and is associated with an increased risk of morbidity and mortality. CKD can be caused by a wide variety of primary renal disorders. In about one in five CKD patients, no primary renal disease diagnosis can be established. Moreover, recent studies indicate that the clinical diagnosis may be incorrect in a substantial number of patients. Both the absence of a diagnosis or an incorrect diagnosis can have therapeutic implications. Genetic testing might increase the diagnostic accuracy in patients with CKD, especially in patients with unknown etiology. The diagnostic utility of NGS has been shown mainly in pediatric CKD cohorts, while emerging data suggest that genetic testing can also be a valuable diagnostic tool in adults with CKD. In addition to its implications for unexplained CKD, NGS can contribute to the diagnostic process in kidney diseases with an atypical presentation, where it may lead to reclassification of the primary renal disease diagnosis. So far, only a few studies have reported on the diagnostic yield of NGS-based techniques in patients with unexplained CKD. Here, we will discuss the potential diagnostic role of gene panels and whole exome sequencing in pediatric and adult patients with unexplained and atypical CKD.

Look Alike, Sound Alike: Phenocopies in Steroid-Resistant Nephrotic Syndrome

“…All these patients received a generic clinical diagnosis of SRNS or FSGS before undergoing genetic analysis [65,72,73,[90][91][92]. From a clinical point of view, the latest progress in the diagnostic algorithm is the possibility to couple extended genetic analysis with reverse phenotyping, enabling a more precise differentiation between overlapping phenotypes and leading to a reclassification of the diagnosis in individual patients [4,90,93]. Indeed, including genes responsible for inherited nephropathies other than monogenic podocytopathies (ideally, all "CKD genes") represents the first step for a correct diagnosis of SRNS.…”

The diagnostic yield of whole exome sequencing as a first approach in consanguineous Omani renal ciliopathy syndrome patients

“…In paediatric populations, CKD is a major contributor to health-care burden leading to severe morbidity and mortality. At least 17% of those with ESKD are considered as CKD with unknown aetiology, where the primary kidney disease is not clear 16 . In addition, the primary clinical diagnosis of CKD patients is often inaccurate 16 .…”

“…At least 17% of those with ESKD are considered as CKD with unknown aetiology, where the primary kidney disease is not clear 16 . In addition, the primary clinical diagnosis of CKD patients is often inaccurate 16 . Thus, in the developing era of precision medicine, WES is used as an essential tool that provides novel diagnostic perspectives for the detection of the causes of CKD.…”

Genetic testing for kidney disease of unknown etiology

“…14 For cases in which secondary or incidental results are undesired, clinicians may consider targeted analysis restricted to genes known to cause CKD. 54 developed such a gene list, 13 a periodically updated version of which can be found at http://www.columbiamedicine.org/ divisions/gharavi/.) If targeted analysis is negative, the clinician may consider broadening to an unrestricted analysis.…”