Genetic Testing in Adults over 50 Years with Chronic Kidney Disease: Diagnostic Yield and Clinical Implications in a Specialized Kidney Genetics Clinic

Abstract

Background: Genetic causes of chronic diseases, once considered rare in adult-onset disease, now account for between 10 and 20% of cases of chronic kidney disease (CKD). Confirming a genetic diagnosis can influence disease management; however, the utility of genetic testing in older adults remains poorly understood, partly due to age-based restrictions on testing access. To better evaluate the diagnostic yield and clinical utility of genetic testing in this population, we analyzed data from adults aged ≥50 years with CKD who were assessed in a specialized kidney genetics clinic. Methods: We studied a cohort of 125 adults with CKD aged ≥50 years at the time of genetic testing. Genetic testing included gene panels targeting disease-related genes based on clinical phenotype, and/or exome sequencing for additional monogenic causes if the initial panel testing was inconclusive. Results: Pathogenic variants in disease-related genes were identified in 38% of patients. The highest diagnostic yield (48%) was in patients aged 50-54 years. The most common diagnosis post-testing was glomerulopathies (32%). Clinical utility, shown through the case series, included modifications to treatment and clinical management, as well as a reduction in the diagnostic odyssey. Conclusions: Our findings from a dedicated Kidney Genetics Clinic show that genetic testing in adults ≥50 years with CKD has significant diagnostic and clinical utility. These results support guideline recommendations that there should be no upper age limit for genetic testing. Future research in unselected CKD populations is needed to establish the broader applicability and feasibility of genetic testing in older adults.

Keywords: chronic kidney disease; exome sequencing; genetic kidney disease; genetic testing; older adults.

Figure 1

Genetic Testing Workflow in a Dedicated Kidney Genetics Clinic. CKD (chronic kidney disease). Referral; referral to the Kidney Genetics Clinic.

Figure 2

Diagnostic yield of chronic kidney disease patients ≥ 50 years of age at time of genetic testing. (A) Overall diagnostic yield (B) Diagnostic yield stratified by age at genetic testing. Participants are either solved with a pathogenic variant, which has definitive evidence of disease causation, or likely pathogenic which have strong but not absolute evidence (>90% certainty) and are both considered diagnostic in clinical genetics [23]. Unsolved participants can either have a VUS (variants of uncertain significance), or no identified variants. Abbreviations: atypical hemolytic uremic syndrome (aHUS), autosomal dominant tubulointerstitial kidney disease (ADTKD), and nephrocalcinosis and nephrolithiasis (NC/NL).

Figure 3

Clinical utility in solved participants (n = 47). Clinical utility is determined by predefined health outcomes, modified from Hayeems et al. [24]. The dark gray represents patients diagnosed with CKD before the age of 50, light gray represents those diagnosed at 50 years or older. The numbers within each bar represent the percent of solved patients with that health outcome for each age group, and the percent at the end of the bar represents the overall percentage of solved patients with the health outcome.