Clinical impact of genomic testing in patients with suspected monogenic kidney disease

Abstract

To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. Methods: We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Results: ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/ 80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). Conclusion: In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.

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

“…Phenocopy genes identified were COL4A3 , COL4A4 , COL4A5 , LAMB2 , GLA , FAT1 , FAT4 , PAX2 , CLCN5 , CTNS , LMX1B and KANK1 [ 4 ]. Very recently, clinical revaluation on the light of genetic findings was performed in selected cases of large cohorts of patients [ 90 , 91 ], confirming the utility of moving back from genotype to phenotype in order to reclassify diseases ( Figure 3 B). Interestingly, similar results have been provided also for other inherited kidney diseases, such as tubulopathies and nephronophthisis [ 68 , 69 , 94 ].…”

“…Interestingly, the term “phenocopy” was used for the first time in this work in the field of SRNS. Following a similar approach, phenocopies of monogenic podocytopathies can actually be found in other studies assessing the role of NGS in nephropathies, either in children or adults [ 65 , 73 , 74 , 90 , 91 , 92 ]. In these studies, unbiased extended genetic testing allowed authors to turn the initial clinical diagnosis into a specific genetic diagnosis.…”

“…Specifically, phenocopies of monogenic podocytopathies were detected at a rate of 1–5%. All these patients received a generic clinical diagnosis of SRNS or FSGS before undergoing genetic analysis [ 65 , 72 , 73 , 90 , 91 , 92 ].…”

“…The high diagnostic capability to reclassify the original diagnosis based on clinical suspicion has also been recently confirmed in a real-life clinical setting by Jayasingh et al, who reported the analysis of the clinical impact of genomic testing in patients with suspected monogenic kidney diseases. In this work, NGS reclassified the clinical diagnosis with direct impact on subsequent clinical management and counseling [ 91 ].…”

“…Specifically, phenocopies of monogenic podocytopathies were detected at a rate of 1-5%. 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].…”