Different Clinical Presentation and Tissue Characterization in a Monozygotic Twin Pair with MYH7 Mutation-Related Hypertrophic Cardiomyopathy

Abstract

This case report demonstrates a pair of monozygotic twins with hypertrophic cardiomyopathy (HCM) carrying the same pathogenic mutation of MYH7 (p.G768R; c.2302G>A), detected by whole exome and Sanger genetic sequencing methods. On multi-modality imaging, they were reported to have similar, but not identical, morphologic expression. Particularly, the clinical presentation and tissue characteristics were not the same. Late gadolinium enhancement (LGE) and T1 mapping of cardiac magnetic resonance showed different extents of myocardial fibrotic characteristics in the twins (twin A: 16.3% LGE and 32.6% extracellular volume [ECV] of the whole left ventricle; twin B: 5.4% LGE and 28.1% ECV of the whole left ventricle). This extraordinary case of HCM provides evidence on the complex pathophysiological mechanisms of HCM and suggests the likely impact of epigenetics and environmental factors on HCM phenotype.

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

“…Disease manifestation is mutation-specific, with patients with different mutations in the same gene showing contrasting clinical outcomes [ 7 ]. Even monozygotic twins bearing the same sarcomeric mutation displayed different clinical presentations [ 8 ], implying that factors beyond the single pathological change (e.g., genetic and epigenetic background and environmental modifiers) contribute to the magnitude of the disease effects [ 9 ]. This intricate clinical and genetic complexity of HCM has impaired the development of efficient therapeutics, with heart transplantation being the only long-term solution [ 10 , 11 ].…”

Discordant clinical features of identical hypertrophic cardiomyopathy twins

“…A classic approach to defining the contribution of genetic and environmental factors to variable progression of human disorders is to compare clinical phenotypes in monozygotic (MZ) twins, who have identical genome sequences. Few case reports have evaluated MZ twins with HCM (17)(18)(19)(20)(21)(22). Wang et al (19) showed that a twin pair with a pathogenic sarcomere gene mutation (MYH7 G768R) had similar LVWT but different amounts of fibrosis, measured by late gadolinium enhanced magnetic resonance imaging.…”

“…Few case reports have evaluated MZ twins with HCM (17)(18)(19)(20)(21)(22). Wang et al (19) showed that a twin pair with a pathogenic sarcomere gene mutation (MYH7 G768R) had similar LVWT but different amounts of fibrosis, measured by late gadolinium enhanced magnetic resonance imaging. Jansweijer et al (22) examined interventricular 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.…”

Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention

“…A limitation of earlier studies employing hPSC-CMs was that the impact of (epi)genetic background on phenotype can exceed that caused by the pathogenic mutation, as evidenced by variations in action potential durations between 100-700 ms among different lines described as 'healthy controls' [69]. This was also verified in patients, as recently reported for monozygotic twins carrying the same mutation (G768-β-MHC) but showing differences in myocardial fibrosis [70].…”