Discordant clinical features of identical hypertrophic cardiomyopathy twins Giuliana G. Repetti a,1 , Yuri Kim a,b,1 , Alexandre C. Pereira c , Jodie Ingles d,e , Mark W. Russell f , Neal K. Lakdawala b , Carolyn Y. Ho b , Sharlene Day g , Christopher Semsarian d,e , Barbara McDonough a,h , Steven R. DePalma a,h , Daniel Quiat a,i , Eric M. Green j , Christine E. Seidman a,b,h,2 , and J. G. Seidman a,2,3 a Department of Genetics, Harvard Medical School, Boston, MA 02115; b Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115; c Heart Institute (InCor), University of Sao Paulo Medical School, 05508-060 Sao Paulo, Brazil; d Department of Cardiology, Royal Prince Alfred Hospital, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; e Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Sydney, NSW 2006, Australia; f Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109; g Division of Cardiovascular Medicine, Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; h Howard Hughes Medical Institute, Chevy Chase, MD 20815; i Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115; and j Maze Therapeutics, South San Francisco, CA 94080 Contributed by J. G. Seidman, January 11, 2021 (sent for review October 27, 2020; reviewed by Libin Wang and Cordula M. Wolf) Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle, which affects ∼1 in 500 individuals and is characterized by in- creased 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 ventric- ular wall thickness, left atrial diameter, and left ventricular ejec- tion 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 morpho- logic features of the heart, demonstrating the influence of non- hereditable 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 epi- genetics and environment in HCM disease progression. hypertrophic cardiomyopathy | identical twins | genetics H ypertrophic cardiomyopathy (HCM) is characterized by left ventricular (LV) hypertrophy accompanied by nondilated ventricular chambers in the absence of other cardiac or systemic disease that would cause similar cardiac morphology (1). HCM is clinically recognized in ∼1 in 500 individuals, and >70% of fa- milial HCM patients carry a pathogenic or likely pathogenic variant in genes encoding cardiac sarcomere proteins (2, 3) (denoted as HCM variants). Most HCM variants alter thick fil- ament proteins myosin heavy chain 7 (MYH7) and myosin binding protein C (MYBPC3). Other HCM variants in genes encoding thin filament proteins, such as troponin T (TNNT2), account for a minority of cases (4, 5). HCM variants generally have high penetrance but produce variable expression of clinical manifestations (6–13). Some var- iant carriers manifest LV hypertrophy early in childhood, while others have normal LV wall thickness (LVWT) until the sixth or seventh decade of life. Hypertrophy can range from the upper limit of normal (LVWT = 12 mm) to massive (>30 mm) and can occur with minimal symptoms, advanced heart failure, or fatal arrhythmias (3, 10). Approximately 25% of patients die from HCM-related adverse events (14), including sudden cardiac death, thromboembolic stroke, and heart failure. Although pa- tients with HCM variants have more adverse outcomes than patients with unknown causes for HCM (15, 16), the mechanisms accounting for diverse responses to variants within the same or different HCM genes are unknown. A classic approach to defining the contribution of genetic and environmental factors to variable progression of human disor- ders is to compare clinical phenotypes in monozygotic (MZ) twins, who have identical genome sequences. Few case reports have evaluated MZ twins with HCM (17–22). Wang et al. (19) showed that a twin pair with a pathogenic sarcomere gene mu- tation (MYH7 G768R) had similar LVWT but different amounts of fibrosis, measured by late gadolinium enhanced magnetic resonance imaging. Jansweijer et al. (22) examined interven- tricular septum thickness (IVSd) from 11 MZ twin pairs with HCM, including 5 pairs with sarcomeric variants, and found no significant heritability for IVSd in HCM. In contrast, a recent study demonstrated concordant morphologic findings and clini- cal course of identical twins with HCM, suggesting little envi- ronmental influence on clinical expression of HCM (20). Whether MZ twins with HCM variants have similar or different clinical courses remains uncertain. To more fully identify factors influencing HCM progression, we characterized longitudinal disease progression in 11 MZ twin pairs, including 9 with path- ogenic sarcomere variants over 5 to 14 y. Significance Genetics, notably pathogenic genetic variants in sarcomere protein genes, play a major role in development of hypertro- phic cardiomyopathy (HCM). However, degree of contribution from epigenetic and environmental factors in clinical presen- tation of HCM is currently unclear. We investigated phenotypic differences between identical twins with pathogenic sarco- mere protein gene variants and demonstrated their discordant HCM presentation despite having virtually identical genomes. Our study underscores the important contribution of epige- netics and environment in disease progression in genetically diagnosed HCM patients. Author contributions: G.G.R., Y.K., C.E.S., and J.G.S. designed research; G.G.R., Y.K., A.C.P., J.I., M.W.R., and J.G.S. performed research; N.K.L., C.Y.H., S.D., C.S., B.M., D.Q., and E.M.G. contributed new reagents/analytic tools; G.G.R., Y.K., A.C.P., J.I., M.W.R., S.R.D., and J.G.S. analyzed data; and G.G.R., Y.K., C.E.S., and J.G.S. wrote the paper. Reviewers: L.W., University of Maryland Medical Center; and C.M.W., German Heart Centre. The authors declare no competing interest. Published under the PNAS license. 1 G.G.R. and Y.K. contributed equally to this work. 2 C.E.S. and J.G.S. contributed equally to this work. 3 To whom correspondence may be addressed. Email: [email protected]. harvard.edu. This article contains supporting information online at https://www.pnas.org/lookup/suppl/ doi:10.1073/pnas.2021717118/-/DCSupplemental. Published March 3, 2021. PNAS 2021 Vol. 118 No. 10 e2021717118 https://doi.org/10.1073/pnas.2021717118 | 1 of 5 GENETICS Downloaded from https://www.pnas.org by 117.3.248.167 on June 21, 2023 from IP address 117.3.248.167.
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