Analysis of diagnostic yield of inherited cardiac arrhythmia gene panels across ethnic groups in the 100,000 Genomes Project

Abstract

IntroductionInherited cardiac arrhythmias (ICAs) including long QT syndrome (LQTS) and Brugada syndrome (BrS) are life-threatening channelopathies caused by mutations in genes encoding cardiac ion channels and their regulators. While ICAs have been studied extensively from a genetic perspective, the distribution of associated variants and diagnostic yield across ethnic groups remains poorly understood. This study aimed to assess the genetic diagnostic efficacy of ICA-associated gene panels across different ethnic populations in the UK using whole genome sequencing data from the 100 000 Genomes Project (100KGP).MethodsWe retrospectively analysed genomic data from individuals diagnosed with LQTS or BrS in the 100KGP, stratifying by self-reported ethnicity. Variants were assessed using both individual disease-specific panels and a combined ICA super panel. We evaluated the distribution of tiered variants and the overall diagnostic yield by ethnic group.ResultsThe combined ICA panel improved equitable identification of tiered variants across ethnicities compared with disease-specific panels, which showed marked disparities. Notably, the BrS-specific panel identified Tier 1–2 variants almost exclusively in white patients. In contrast, the ICA panel revealed a broader distribution of potentially pathogenic variants among non-white populations, with black patients with BrS showing a significantly higher tiered variant rate compared with white patients.ConclusionWe conclude that the distribution of Tier 1–2 variants associated with LQTS/BrS significantly varied across ethnicities. These findings support the expansion of diagnostic panels to include a broader set of ICA-related genes and consideration of ethnicity to improve equity in genomic medicine.