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Study examines Discordant Clinical Features in Identical Twins with Heritable Hypertrophic Cardiomyopathy

The most common of the heritable cardiomyopathies, hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy. Inherited HCM is autosomal dominant and is caused by mutations in genes encoding the cardiac sarcomere proteins in most affected persons (~50%%). To date, more than 1000 of these mutations have been identified in 11 distinct components of the sarcomere. In addition to its genetic constituent, HCM is thought to be influenced by epigenetic and environmental mechanisms. Long a source of interest and study, these factors and their interaction in HCM have yet to be fully defined.

Studies in identical twins have been used to define the roles of environment and heritability in diseases with a suspected genetic element for more than a century, and have a particular application in heritable HCM. This is, in part, because HCM has been observed to manifest with great variability of expression in individuals of the same family—including monozygotic twins—carrying the same mutation.

Investigating the divergent clinical features of identical twins with HCM was the object of a multi-center study co-authored by Sharlene Day, MD, of Penn’s Center for Inherited Cardiac Disease. Dr. Day is the Director of Translational Research in the Division of Cardiovascular Medicine and Cardiovascular Institute. The study sought to determine whether genetic variation or environmental factors were contributing to differences in HCM clinical expression among individuals with the same pathogenic variants of the disease.

In achieving this objective, the study examined disease progression in 11 pairs of monozygotic HCM twins, who ranged in age from 4.5 years to 52 years at age of diagnosis. The twins were followed for 5 to 14 years, during which information relevant to HCM progression (left wall thickness, left atrial diameter, and left ventricular ejection fraction) was collected from echocardiograms at various timepoints.

Following a series of analyses of cardiac morphology and function, left ventricular wall thickness (LVWT) discordances were found in all of the twin pairs despite their identical genomes, suggesting the influence of non-hereditable (e.g. epigenetic and environmental) factors in the clinical expression of HCM, in addition to background genetic variation.

Of these findings, study co-author Dr. Day commented, “The challenge now is trying to define precisely what the environmental and epigenetic drivers are that account for discordant disease evolution and trajectory in genetically identical individuals who carry the same primary sarcomere variant. For older individuals, environmental influences are probably stronger -- co-morbid conditions, like hypertension and obesity. But for pediatric patients, as yet undefined epigenetic or developmental factors likely play a stronger disease modifying role.”

The report underscores the important contribution of epigenetics and environment in disease progression in genetically diagnosed HCM patients, and are a relevant addition to the few available case reports of monozygotic twins with HCM.

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