Discordant clinical features of identical hypertrophic cardiomyopathy twins

Abstract

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.

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

“…In addition to molecular mechanisms (including genetic factors), other factors can affect the clinical course and presentations of HCM. Environmental and lifestyle factors, most probably via epigenetic mechanisms, influence HCM phenotype [ 97 , 98 , 99 ]. These factors and their interaction in HCM have yet to be fully defined but might include microbial infection, diet [ 97 ], or exercise [ 96 , 97 , 98 ].…”

“…Environmental and lifestyle factors, most probably via epigenetic mechanisms, influence HCM phenotype [ 97 , 98 , 99 ]. These factors and their interaction in HCM have yet to be fully defined but might include microbial infection, diet [ 97 ], or exercise [ 96 , 97 , 98 ]. A study by Repetti et al suggested that epigenetic and environmental factors, rather than background genetic variation, play a major role in hypertrophic remodeling [ 97 ].…”

What Causes Hypertrophic Cardiomyopathy?

“…Ventricular septal thickness on echocardiographic imaging differs substantially in the twins. Reproduced from Repetli GG, et al 28 with permission. (D) Network features, emphasizing that network connections represent functionally important protein-protein interactions (PPIs).…”

Experience in genetic testing of hypertrophic cardiomyopathy using nanopore DNA sequencing

“…Сложность выявления генетической компоненты ГКМП и оценки патогенетической значимости отдельных генетических вариантов обусловлена тем, что для ГКМП характерны неполная возраст-зависимая пенетрантность и вариабельность клинического течения даже у обладателей одного и того же патологического варианта; пенетрантность мутации может различаться в т.ч. и у близнецов [3].…”