Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study

Abstract

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results (RoR) is unclear. In addition, the majority of discovered variants are currently classified as Variants of Uncertain Significance (VUS), limiting clinical actionability. Methods: The eMERGE-III study is a multi-center prospective cohort which included 21,846 participants without prior indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with Electronic Health Record (EHR)-derived phenotypes and follow-up clinical examination. Selected VUS (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had pathogenic or likely pathogenic (P/LP) variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared to non-carriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their EHRs. Fifty four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 12/19 of these diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and in vitro functional studies.

Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics

“…Our study provides the first assessment of the cardiovascular population prevalence of P/LP variants in arrhythmia-related genes across all arrhythmogenic disorders. The estimated prevalence for each arrhythmogenic disorder in CATHGEN is comparable to prior population-based assessments of genotype positivity for ARVC, BrS, HCM, LMNA -related cardiomyopathy, and LQTS in previously published cohorts 6,9,10,12–14 after American College of Genetics and Genomics/Association for Molecular Pathology classification is applied to the variants identified in those cohorts (Table S7).…”

1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants

“…This argument was very well emphasised by a recent multi-centre cohort study in which 10 arrhythmia genes were screened in > 20,000 participants without any indication for arrhythmia disorders. About 0.6% of individuals carried P/LP variants and diagnosis could be made after variant results were returned in 0.05% of the cases [49]. For the present study, we acknowledge the fact that genomic dataset of 1029 individuals is very small for a country of 1.3 billion people, nevertheless, our study only serves as the starting point in the direction to derive Indian population-specific genotypic prevalence estimates for cardiac ion channelopathy disorders.…”

First Steps of Population Genomic Medicine in the Arrhythmia World: Pros and Cons

“…4 The same group, running the eMERGE-III project, extended their previous attempt and have now studied almost 22 000 individuals (Figure [A]). 3 The 6 aforementioned genes and 4 other "non-ACMG genes" (KCNE1, KCNE2, ANK2, CACNA1C) were screened and linked to the EHR. A total of 120 participants (0.6%) harbored an apparent P/LP variant in 1 of these 10 genes, and these individuals were more likely to have evidence for an arrhythmia phenotype in their EHR.…”

“…The latest study from the eMERGE (Electronic Medical Records and Genomics) consortium in this issue seeks to address these issues by evaluating the association of pathogenic variants with arrhythmia phenotypes in a large multicenter prospective cohort and the effect of reporting these findings on subsequent clinical diagnoses. 3 In the first attempt of the eMERGE consortium to link putative pathogenic variants in KCNH2 and SCN5A to arrhythmia phenotypes recorded in the EHRs, almost no arrhythmia diagnoses were made in 2022 individuals in whom drugs with potentially significant drug-related side effects (proarrhythmia excluded) were prescribed. 4 Furthermore, with respect to the return of result policy, a disturbing discordance in mutation calling became evident, as 3 genotyping companies and the ClinVar database had full agreement on the status of the variant in only 2 out of 42 variants.…”