BACKGROUND Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. METHODS Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data. RESULTS Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM. CONCLUSIONS This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

中文翻译：

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低外显率肌节变异导致肥厚型心肌病的累加性风险。


背景 传统上，肥厚型心肌病 （HCM） 被视为由肌节基因致病性变异引起的单基因（单基因）疾病。致病性肌节变异个体罕见，并且具有发生 HCM （高度渗透性） 的高风险。最近，重要的多基因贡献也被表征了。尚未系统地研究中频和效应大小的低外显率肌节变体 （LowSVs）。我们假设 LowSVs 可能在 HCM 中很常见，对疾病风险和严重程度有重大影响。方法 在肌节人类心肌病登记处 （SHaRe） 中观察到的所有肌节变异中，我们确定了推定的低 SVs，定义为 （1） 高渗透（单基因）HCM 的群体频率大于预期 （等位基因频率 >5×10-5 在基因组聚集数据库中，gnomAD） 和 （2） 与 gnomAD 相比，HCM 患者的中度富集 （>2×）。检查了 LowSVs 与疾病严重程度和临床结局的相关性。使用诱导多能干细胞衍生的心肌细胞评估所选 LowSVs 的功能影响。使用英国生物样本库心脏磁共振成像数据测试了 LowSVs 与普通人群中 HCM 相关性状的关联。结果 在 6045 例患者和 1159 个肌节基因独特变异中，鉴定出 12 个 LowSVs。低 SVs 在普通人群中普遍存在 （1：350），在 HCM 中适度丰富 （总比值比，14.9 [95% CI，12.5-17.9]）。孤立的 LowSVs 与 HCM 诊断年龄较大和不良事件较少相关。然而，LowSVs 与致病性肌节变异联合给药时发病率更高（例如，复合不良事件风险比，5.4 [95% CI，3.0-9。8] 与单一致病性肌节变异相比，2.0 [95% CI，1.8-2.2];P<0.001）。验证了 2 个特定的 LowSVs-MYBPC3 c.442G>A （部分剪接增益） 和 TNNT2 c.832C>T （对收缩力学的中间影响） 的中间功能影响。对普通人群的心脏磁共振成像分析显示，12 例 LowSVs 中有 5 例与 HCM 相邻性状显著相关，而没有明显的 HCM。结论 本研究确定了一类在人群中相对常见的新低外显率肌节变异。当渗透性强时，孤立的 LowSVs 会导致轻度 HCM。与致病性肌节变体联合使用，LowSVs 显着增加疾病严重程度，支持临床上显着的累加效应。最后，即使在没有明显的 HCM 的情况下，LowSVs 也有助于与年龄相关的重塑。