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

Abstract

Purpose: 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.

Keywords: chronic kidney disease; exome sequencing; genetic kidney disease.

Fig. 1. Workflow of the multidisciplinary renal genetics clinic (RGC), from recruitment to result return.

Referral received by nephrologist involved in multidisciplinary RGC. Triage of referral by multidisciplinary team (MDT) consisting of nephrologist/s, clinical geneticist, and genetic counselor. Patient attends for clinic appointment for clinical review, pretest genetic counseling, and consent. Sample collected at local hospital. Genomic data isolated from blood and saliva samples. Clinically accredited genomic sequencing performed. Initial computational bioinformatics analysis. Variant prioritization meeting to prioritize variants for assessment, using a tiered approach, attended by a senior medical genomic scientist, clinical geneticists, lead nephrologist, referring nephrologist from RGC, and genetic counselors. Variant curation as per American College of Medical Genetics and Genomics (ACMG) guidelines. Review of variant and phenotypic data by MDT of laboratory scientists, clinical geneticists, nephrologists from the RGC and genetic counselors to reach consensus prior to reporting and ensure that genotype is concordant with phenotype. Patient attends clinic appointment for return of results with post-test genetic counseling, with segregation encouraged (where appropriate), suitable patients flagged for recruitment into research. *See “Materials and Methods” for details, including outlined of tiered approach to testing.

Fig. 2. Flowchart of recruitment and results.

CMA chromosomal microarray, ES exome sequencing.