{'fraction_non_alphanumeric': 0.013567839195979899, 'fraction_numerical': 0.004522613065326633, 'mean_word_length': 6.085409252669039, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Discordant clinical features of identical hypertrophic cardiomyopathy twins

Significance Genetics, notably pathogenic genetic variants in sarcomere protein genes, play a major role in development of hypertrophic cardiomyopathy (HCM). However, degree of contribution from epigenetic and environmental factors in clinical presentation of HCM is currently unclear. We investigated phenotypic differences between identical twins with pathogenic sarcomere protein gene variants and demonstrated their discordant HCM presentation despite having virtually identical genomes. Our study underscores the important contribution of epigenetics and environment in disease progression in genetically diagnosed HCM patients. 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.