Revisiting the Genetics of Hypertrophic Cardiomyopathy: From Sarcomeres to Polygenic Modulation and Clinical Translation

Figures

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  Figure 1. From monogenic disease to near-Mendelian and polygenic hypertrophic cardiomyopathy. Panel (A) illustrates the traditional monogenic model of HCM, in which a single pathogenic variant in a sarcomeric gene (most commonly MYH7 or MYBPC3) is considered sufficient to cause disease (“one gene–one disease”). Panel (B) depicts the contemporary, more complex model, whereby a rare sarcomeric pathogenic variant represents the primary genetic substrate but disease penetrance and expressivity are modulated by additional factors, including other rare variants, the polygenic background, and environmental or clinical modifiers, resulting in a continuum of HCM risk. Panel (C) summarizes the resulting phenotypic spectrum, ranging from genotype-positive/phenotype-negative individuals, through classic sarcomeric HCM, to HCM-like phenotypes and phenocopies driven by distinct molecular mechanisms. This framework highlights that genotype alone is insufficient to fully explain disease expression and supports an integrated, phenotype-anchored approach to clinical interpretation.

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  Figure 2. Sarcomeric HCM in a genetically characterized patient. Comprehensive molecular analysis of an 80-gene cardiomyopathy panel identified a pathogenic heterozygous variant in TNNI3 and a heterozygous VUS in CAV3. Apical four-chamber echocardiographic views obtained in diastole (Panel (A)) and systole (Panel (B)) demonstrate moderate asymmetric septal and apical hypertrophy (interventricular septum 15 mm, apical thickness 13 mm, posterior wall 10 mm), with preserved global systolic function (LVEF 56%). Panel (C) shows a dynamic left ventricular outflow tract (LVOT) gradient, increasing from 15 mmHg at rest to 47 mmHg during Valsalva maneuver, with the characteristic dagger-shaped Doppler profile. Panel (D) displays a 12-lead ECG revealing an atrial paced rhythm from a pacemaker programmed in AAI mode at 60 bpm, along with electrocardiographic signs of left ventricular hypertrophy with strain pattern.

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  Figure 3. Non-obstructive HCM in a genetically negative patient. The patient underwent serial genetic testing over time using progressively expanded panels. A comprehensive molecular analysis of 174 cardiomyopathy-associated genes identified a heterozygous VUS in LAMA4. Expansion of the genetic panel did not result in any change in diagnosis or clinical management. Panel (A). Transthoracic echocardiography shows a normal-sized left ventricle with severe asymmetric septal hypertrophy (anterior IVS 20 mm; posterior IVS 18 mm), preserved global systolic function (biplane Simpson LVEF 63%), and no regional wall motion abnormalities. Apical hypertrabeculation is noted. Panel (B). Twelve-lead ECG demonstrates sinus rhythm at 62 bpm, first-degree atrioventricular block (PR interval 220 ms), left anterior fascicular block, and electrocardiographic signs of left ventricular hypertrophy. Poor R-wave progression from V1 to V4 is observed.

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  Figure 4. Multilayered genetic architecture of hypertrophic cardiomyopathy. Sarcomeric genes with definitive or strong gene–disease validity (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1) represent the core monogenic substrate of HCM. Surrounding this central axis, multiple additional layers modulate disease penetrance and expressivity. These include emerging HCM-associated genes (e.g., ALPK3, FHOD3, JPH2), rare and intermediate-effect genetic modifiers, and the polygenic background captured by genetic risk scores, which collectively influence disease susceptibility and phenotypic severity. Non-genetic factors, including lifestyle, environmental exposures, and epigenetic mechanisms, further contribute to interindividual variability. The interaction among these components results in age-dependent penetrance and a broad spectrum of clinical expressivity, supporting a near-Mendelian and oligogenic model of HCM rather than a strictly deterministic monogenic disease.

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  Figure 5. Reclassification from genotype-negative HCM to wild-type transthyretin cardiac amyloidosis (ATTRwt). The patient was initially diagnosed with genotype-negative HCM. Subsequent multimodality evaluation led to the diagnosis of wild-type transthyretin cardiac amyloidosis (ATTRwt). Panel (A): Apical four-chamber echocardiographic view showing a left ventricle with preserved internal dimensions and severe, diffuse, uniform wall thickening, including papillary muscle hypertrophy, with a characteristic “ground-glass” myocardial appearance. Moderate global systolic dysfunction is present (biplane Simpson LVEF 46%), mainly due to marked hypokinesia of basal segments. The left atrium is severely dilated. The interatrial septum appears thickened and hyper-reflective. The mitral valve leaflets are thickened and stiff, with chordal calcifications. Panel (B): Twelve-lead ECG demonstrating a ventricular paced rhythm from a pacemaker programmed in DDD mode at 50 bpm. Panel (C): Echocardiographic assessment of the right ventricle revealing right ventricular systolic dysfunction (TAPSE 13 mm). Panel (D): Myocardial deformation analysis showing a moderately reduced global longitudinal strain (GLS…

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  Figure 6. Echocardiographic findings in a young patient with Fabry disease. Panel (A). Parasternal long-axis view showing a left ventricle with normal internal dimensions and mildly increased wall thickness, predominantly involving the mid and apical inferior, inferolateral, and lateral segments (maximum wall thickness 14 mm; interventricular septum 9 mm; posterior wall 9 mm). Global systolic function is at the lower limit of normal (biplane Simpson LVEF 52%). No regional wall motion abnormalities are observed. Panel (B). Apical four-chamber view with apical zoom confirming preserved LV cavity size and mild segmental hypertrophy, particularly the apex. Panel (C). Myocardial deformation analysis demonstrating impaired longitudinal function with a reduced global longitudinal strain (GLS −16.9%).

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  Figure 7. Findings in a patient with biventricular HCM. Panels (A,B) (cine CMR views): Severe asymmetric left ventricular hypertrophy with a mid-apical distribution, associated with preserved ventricular volumes and systolic function. Concomitant mid-apical right ventricular hypertrophy is observed, with preserved right ventricular volumes and systolic performance. Panels (C,D): Increased native T1 values, consistent with diffuse myocardial tissue abnormalities. Panels (E,F): Myocardial signal hyperintensity on T2-weighted images involving the mid IVS. T2 mapping demonstrates elevated T2 values at the level of the anterior wall and the interventricular septum, predominantly in the basal segments, as well as in the mid and apical inferior septum, suggestive of myocardial edema/inflammatory involvement.