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Alport Syndrome (AS), particularly autosomal dominant AS, can range in severity from microscopic hematuria to end-stage kidney disease (ESKD), and often goes undiagnosed. With increased availability of genetic testing and recognition of the importance of AS in chronic kidney disease (CKD), there is a need to understand the molecular diagnostic yield across various phenotypes and settings. We hypothesized that the molecular diagnostic yield would be lower in largely unselected health system cohorts compared to a multidisciplinary renal genetics cohort.
Molecular diagnostic yield was examined in 3 different cohorts, including two health system-based research cohorts, Geisinger MyCode in central/northeast Pennsylvania and Mass General Brigham Biobank (MGBB) in Boston, Massachusetts, and a clinical cohort from a multidisciplinary renal genetics clinic in Melbourne, Australia. Diagnoses of Alport Syndrome-related phenotypes were defined locally at each site using electronic health record (EHR) data for MyCode and MGBB and via indication for genetic testing for the Australian clinical cohort. Diagnostic yield was defined as having a variant previously classified in ClinVar as pathogenic or likely pathogenic, or a glycine collagenous domain variant, or protein truncating variant using recommendations per Alport Syndrome consensus statement guidelines (Savige et al. PMID 33854215) at each site.
Diagnostic yield was highest in the clinical cohort and lower in the broader health system-based cohorts and varied depending on the severity of the AS phenotype (Table). For example, among individuals <30 years of age presenting with hematuria in the Australian clinical cohort, AS diagnostic yield was 33% whereas it was only 1-2% in patients with ICD diagnoses of hematuria in MyCode and MGBB. In MyCode more expanded phenotyping revealed prevalence of AS P/LP variants >10% for several phenotypic presentations in those <30 years of age, including dipstick hematuria with ACR ≥300 mg/g, dipstick hematuria with family history of CKD, eGFR<60 with family history of CKD, and focal segmental glomerulosclerosis. Diagnostic yield was similar for those with AS ICD diagnoses in MyCode as those with suspected AS in the Australian clinical cohort.
Molecular diagnostic yield for AS varies greatly among phenotypic presentations suggestive of AS and by age. These results suggest that genetic testing should be considered in many individuals <30 years of age with more subtle phenotypic features of AS.