Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle, which affects ∼1 in 500 individuals and is characterized by increased left ventricular wall thickness. While HCM is caused by pathogenic variants in any one of eight sarcomere protein genes, clinical expression varies considerably, even among patients with the same pathogenic variant. To determine whether background genetic variation or environmental factors drive these differences, we studied disease progression in 11 pairs of monozygotic HCM twins. The twin pairs were followed for 5 to 14 y, and left ventricular wall thickness, left atrial diameter, and left ventricular ejection fraction were collected from echocardiograms at various time points. All nine twin pairs with sarcomere protein gene variants and two with unknown disease etiologies had discordant morphologic features of the heart, demonstrating the influence of nonhereditable factors on clinical expression of HCM. Whole genome sequencing analysis of the six monozygotic twins with discordant HCM phenotypes did not reveal notable somatic genetic variants that might explain their clinical differences. Discordant cardiac morphology of identical twins highlights a significant role for epigenetics and environment in HCM disease progression.

肥厚性心肌病 (HCM) 是一种心肌疾病，每 500 人中就有 1 人受到影响，其特征是左心室壁厚度增加。虽然 HCM 是由八个肌节蛋白基因中的任何一个的致病变异引起的，但临床表现差异很大，即使在具有相同致病变异的患者中也是如此。为了确定背景遗传变异或环境因素是否导致这些差异，我们研究了 11 对同卵 HCM 双胞胎的疾病进展。这对双胞胎被随访 5 至 14 年，并从不同时间点的超声心动图中收集左心室壁厚度、左心房直径和左心室射血分数。所有九对具有肌节蛋白基因变异的双胞胎和两对具有未知疾病病因的双胞胎都具有不一致的心脏形态特征，证明了非遗传因素对 HCM 临床表现的影响。对六对 HCM 表型不一致的同卵双胞胎进行全基因组测序分析，未发现可解释其临床差异的显着体细胞遗传变异。同卵双胞胎的不一致心脏形态突出了表观遗传学和环境在 HCM 疾病进展中的重要作用。