👤 Matthew Lebo

Pathogenic variants associated with inherited cardiomyopathy are recognized as important and clinically actionable when identified, leading some clinicians to recommend population-wide genomic screening. To determine the prevalence and clinical importance of pathogenic variants associated with inherited cardiomyopathy within the context of contemporary clinical care. This was a genetic association study of participants in Atherosclerosis in Risk Communities (ARIC), recruited from 1987 to 1989, with median follow-up of 27 years, and the UK Biobank, recruited from 2006 to 2010, with median follow-up of 10 years. ARIC participants were recruited from 4 sites across the US. UK Biobank participants were recruited from 22 sites across the UK. Participants in the US were of African and European ancestry; those in the UK were of African, East Asian, South Asian, and European ancestry. Statistical analyses were performed between August 1, 2021, and February 9, 2022. Rare genetic variants predisposing to inherited cardiomyopathy. Pathogenicity of observed DNA sequence variants in sequenced exomes of 13 genes (ACTC1, FLNC, GLA, LMNA, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2, TPM1, and TTN) associated with inherited cardiomyopathies were classified by a blinded clinical geneticist per American College of Medical Genetics recommendations. Incidence of all-cause mortality, heart failure, and atrial fibrillation were determined. Cardiac magnetic resonance imaging, echocardiography, and electrocardiogram measures were assessed in a subset of participants. A total of 9667 ARIC participants (mean [SD] age, 54.0 [5.7] years; 4232 women [43.8%]; 2658 African [27.5%] and 7009 European [72.5%] ancestry) and 49 744 UK Biobank participants (mean [SD] age, 57.1 [8.0] years; 27 142 women [54.5%]; 1006 African [2.0%], 173 East Asian [0.3%], 939 South Asian [1.9%], and 46 449 European [93.4%] European ancestry) were included in the study. Of those, 59 participants (0.61%) in ARIC and 364 participants (0.73%) in UK Biobank harbored an actionable pathogenic or likely pathogenic variant associated with dilated or hypertrophic cardiomyopathy. Carriers of these variants were not reliably identifiable by imaging. However, the presence of these variants was associated with increased risk of heart failure (hazard ratio [HR], 1.7; 95% CI, 1.1-2.8), atrial fibrillation (HR, 2.9; 95% CI, 1.9-4.5), and all-cause mortality (HR, 1.5; 95% CI, 1.1-2.2) in ARIC. Similar risk patterns were observed in the UK Biobank. Results of this genetic association study suggest that approximately 0.7% of study participants harbored a pathogenic variant associated with inherited cardiomyopathy. These variant carriers would be challenging to identify within clinical practice without genetic testing but are at increased risk for cardiovascular disease and all-cause mortality. Show less

As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing. Forty-one patients with hypertrophic cardiomyopathy who had undergone targeted hypertrophic cardiomyopathy genetic testing (either multigene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants, panel genetic testing identified variants classified as pathogenic, likely pathogenic, or uncertain significance. WGS identified 19 of these 20 variants, but the variant detection algorithm missed a pathogenic 18 bp duplication in myosin binding protein C ( WGS detected nearly all variants identified on panel testing, provided 1 new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical use and numerous secondary genetic findings were also identified. Whereas panel testing and WGS provided similar diagnostic yield, WGS offers the advantage of reanalysis over time to incorporate advances in knowledge, but requires expertise in genomic interpretation to appropriately incorporate WGS into clinical care. URL: https://clinicaltrials.gov. Unique identifier: NCT01736566. Show less