The yield on re-interpretation of genetic variants in pediatric cardiomyopathy
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Background
Variant interpretation can change over time as new knowledge emerges. Our aim was to determine the frequency and causes of variant reinterpretation on systematic re-evaluation in pediatric patients with cardiomyopathy.
Methods
Overall, 227 unrelated pediatric patients with cardiomyopathy enrolled in the Heart Centre Biobank harbored a pathogenic/likely pathogenic (P/LP) variant and/or a variant of uncertain significance (VUS) on clinical genetic testing (2005-2022). Variant pathogenicity was re-evaluated using the American College of Medical Genetics and Genomics (ACMG) guidelines. Additional extension cohorts (n=4547, cases) were analyzed to assess variant burden in cases versus controls (gnomAD 4.1.0).
Results
382 variants (110 P/LP, 272 VUS) in 227 patients were re-evaluated. Forty-nine variants in 49 patients (21.6%) changed classification. Twelve (10.9%) P/LP variants were downgraded to VUS in 14 patients. Leading criteria were high population allele frequency and variant not located in mutational hotspot or critical functional gene domain. Thirty-seven (13.6%) VUS were upgraded to P/LP in 35 patients. Leading criteria were variant location in mutational hotspot for gene, and deleteriousness on in silico prediction. Only 8 reclassified variants had been reported back by the clinical genetic testing laboratory at the time of the study. Ten of the 37 VUS upgraded to P/LP were significantly enriched in cardiomyopathy cases (n=4796) versus controls.
Conclusions
One in five patients with cardiomyopathy had a clinically relevant change in variant pathogenicity on systematic re-evaluation that would require modifying family clinical screening and cascade genetic testing. These findings underscore the clinical importance of regular variant re-interpretation on follow-up.