Charlotte Burns1, Richard D Bagnall1, Lien Lam1, Christopher Semsarian1, Jodie Ingles2. 1. From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (C.B., R.D.B., L.L., C.S., J.I.); Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia (C.B., R.D.B., C.S., J.I.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.B., C.S., J.I.). 2. From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (C.B., R.D.B., L.L., C.S., J.I.); Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia (C.B., R.D.B., C.S., J.I.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.B., C.S., J.I.). j.ingles@centenary.org.au.
Abstract
BACKGROUND: Multiple likely pathogenic/pathogenic (LP/P; ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels. METHODS AND RESULTS: Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ≤0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; P=0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3-9.9; P=0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank P=0.008). CONCLUSIONS: No proband had multiple LP/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy.
BACKGROUND: Multiple likely pathogenic/pathogenic (LP/P; ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels. METHODS AND RESULTS: Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ≤0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; P=0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3-9.9; P=0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank P=0.008). CONCLUSIONS: No proband had multiple LP/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy.
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Authors: Ana Morales; Alexander Ing; Christian Antolik; Christina Austin-Tse; Linnea M Baudhuin; Lucas Bronicki; Allison Cirino; Megan H Hawley; Michael Fietz; John Garcia; Carolyn Ho; Jodie Ingles; Olga Jarinova; Tami Johnston; Melissa A Kelly; C Lisa Kurtz; Matt Lebo; Daniela Macaya; Lisa Mahanta; Joseph Maleszewski; Arjun K Manrai; Mitzi Murray; Gabriele Richard; Chris Semsarian; Kate L Thomson; Tom Winder; James S Ware; Ray E Hershberger; Birgit H Funke; Matteo Vatta Journal: J Mol Diagn Date: 2021-02-22 Impact factor: 5.568