Burns Charlotte, Bagnall Richard D, Lam Lien, Semsarian Christopher, Ingles Jodie
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.).
Circ Cardiovasc Genet. 2017 Aug;10(4). doi: 10.1161/CIRCGENETICS.116.001666.
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.
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; =0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3-9.9; =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 =0.008).
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.
10年前曾描述肥厚型心肌病患者中存在多个可能致病/致病（LP/P；≥2个）变异，患病率为5%。我们试图在综合和靶向基因检测背景下重新审视肥厚型心肌病患者中多个罕见变异的意义。
在758例肥厚型心肌病先证者中，我们纳入了382例筛查了≥45个心肌病相关基因的患者。其中224例（59%）有≥1个罕见变异（等位基因频率≤0.02%）。使用不同大小的基因检测板分析变异，以代表综合或靶向检测。基于45基因检测板，127例（33%）有LP/P变异，139例（36%）有意义未明的变异，66例（17%）有多个罕见变异。一个靶向8基因检测板检测出125例（32%）LP/P变异，52例（14%）意义未明的变异，14例（4%）有多个罕见变异。没有先证者有2个LP/P变异。纳入受影响的家庭成员（共412例），聚类调整分析确定了一种表型效应，在考虑8基因检测板而非更大检测板时，多变异患者比单变异患者更易出现年龄较小（比值比，0.95；95%置信区间，0.92 - 0.98；P = 0.004）和心源性猝死家族史（比值比，3.5；95%置信区间，1.3 - 9.9；P = 0.02）。多变异患者在全因死亡、心脏移植和心脏骤停方面的无事件生存率较差（对数秩检验P = 0.008）。
与既往报道不同，没有先证者有多个LP/P变异。然而，4%的患者存在多个罕见变异，无论其分类如何，这些变异导致疾病更早发生和心脏事件。我们的研究结果支持肥厚型心肌病的累积变异假说。
