RESUMEN
BACKGROUND: Thousands of genetic variants have been identified in cardiomyopathy-associated genes. Diagnostic genetic testing is key for evaluation of individuals with suspected cardiomyopathy. While accurate variant pathogenicity assignment is important for diagnosis, the frequency of and factors associated with clinically relevant assessment changes are unclear. OBJECTIVES: The authors aimed to characterize pathogenicity assignment change in cardiomyopathy-associated genes and to identify factors associated with this change. METHODS: We identified 10 sarcomeric and 6 desmosomal genetic cardiomyopathy-associated genes along with comparison gene sets. We analyzed clinically meaningful changes in pathogenicity assignment between any of the following: pathogenic/likely pathogenic (P/LP), conflicting interpretations of pathogenicity or variant of unknown significance (C/VUS), and benign/likely benign. We explored association of minor allele frequency (MAF) differences between well, and traditionally poorly, represented ancestries in genetic studies with assessment stability. Analyses were performed using ClinVar and GnomAD data. RESULTS: Of the 30,975 cardiomyopathy-associated gene variants in ClinVar, 2,276 of them (7.3%) had a clinically meaningful change in pathogenicity assignment over the study period, 2011 to 2021. Sixty-seven percent of variants that underwent a clinically significant change moved from P/LP or benign/likely benign to C/VUS. Among cardiomyopathy variants downgraded from P/LP, 35% had a MAF above 1 × 10 -4 in non-Europeans and below 1 × 10 -4 in Europeans. CONCLUSIONS: Over the past 10 years, 7.3% of cardiomyopathy gene variants underwent a clinically meaningful change in pathogenicity assignment. Over 30% of downgrades from P/LP may be attributable to higher MAF in Non-Europeans than Europeans. This finding suggests that low ancestral diversity in genetic studies has increased diagnostic uncertainty in cardiomyopathy gene variants.
RESUMEN
Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype-negative. Whole-exome sequencing identified a missense T223M variant in TBX5 that cosegregates with prolonged QT interval in a family with otherwise genotype-negative LQTS and sudden death. The TBX5-T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by in silico modeling based on Panther, PolyPhen-2, Provean, SIFT, SNAP2, and PredictSNP prediction tools. The variant was located in a highly conserved region of TBX5 predicted to be part of the DNA-binding interface. A luciferase assay identified a 57.5% reduction in the ability of TBX5-T223M to drive expression at the atrial natriuretic factor promotor compared to wildtype TBX5 in vitro. We conclude that the variant is pathogenic in this family, and we put TBX5 forward as a disease susceptibility allele for genotype-negative LQTS. The identification of this familial variant may serve as a basis for the identification of previously unknown mechanisms of LQTS with broader implications for cardiac electrophysiology.
