Can Left Ventricular Hypertrophy Be Genetic?
Yes, LVH can absolutely be genetic, particularly in the form of hypertrophic cardiomyopathy (HCM), which is caused by autosomal dominant mutations in genes encoding cardiac sarcomere proteins and represents one of the most common genetic cardiovascular diseases with a prevalence of approximately 1:500 in the general population. 1
Genetic Forms of LVH
Hypertrophic Cardiomyopathy (Primary Genetic LVH)
HCM is fundamentally a genetic disease caused by autosomal dominant mutations in genes encoding sarcomere protein components, with over 1,400 mutations identified across at least 8 genes. 1
Approximately 30-60% of patients with clinically diagnosed HCM have an identifiable pathogenic or likely pathogenic genetic variant in sarcomere genes. 1
The most commonly affected genes include those encoding cardiac myosin-binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), and alpha-tropomyosin (TPM1). 2
First-degree relatives of HCM patients have a 50% risk of carrying the pathogenic mutation due to autosomal dominant inheritance. 3
Heritability of LV Mass as a Quantitative Trait
Even in non-HCM populations, LV mass demonstrates substantial heritability (h² = 0.3 to 0.7) across different ethnic groups, indicating robust genetic influences on LVH independent of sarcomere mutations. 4, 5
This suggests that genetic factors contribute to common forms of LVH beyond monogenic HCM, though specific genes and functional variants remain largely unidentified. 5
Genetic LVH in Pediatric Patients
Age-Related Penetrance and Development
In children with HCM-causing mutations, LVH may not be present at birth or early childhood but develops spontaneously during periods of rapid body growth, particularly during adolescence. 1, 6
Serial echocardiographic studies demonstrate that LV wall thickness can increase dramatically (by 6-23 mm, representing 101 ± 62% increases) in children with HCM during follow-up periods, far exceeding changes expected from normal growth (13 ± 10%). 6
A single normal echocardiogram in childhood does not exclude genetic HCM, as morphologic expression is often delayed and incomplete until physical maturity is achieved around age 17-18 years. 1
Pediatric Diagnostic Criteria
In children, HCM diagnosis requires a z-score ≥2 standard deviations above the mean for age, sex, and body size (compared to the absolute 15 mm threshold in adults). 1
For children with definitive family history or positive genetic testing, a lower threshold of z-score >2 is sufficient for early diagnosis, while asymptomatic children without family history should meet a z-score >2.5 threshold. 1
The pediatric z-score of 2 represents a significantly lower threshold than the adult 15 mm criterion, which corresponds to approximately 6 standard deviations above the mean in adults. 1
Genotype-Positive/Phenotype-Negative Status
Children and even adults can carry pathogenic HCM mutations without demonstrating LVH on echocardiography, a state termed "genotype-positive/phenotype-negative." 1
These individuals should be considered at risk for subsequent development of HCM but do not yet have clinically evident disease. 1
Certain mutations, particularly in the cardiac myosin-binding protein C gene (MYBPC3), demonstrate age-related penetrance with delayed onset of LVH appearing in mid-life or even later. 1
Other Genetic Syndromes Causing LVH in Children
Metabolic and Storage Diseases
Multiple genetic metabolic disorders cause LVH that mimics HCM but requires different management strategies, including:
These conditions should not be labeled as HCM because the pathophysiologic mechanisms, natural history, and treatment strategies differ fundamentally from sarcomeric HCM. 1
Malformation Syndromes
RASopathies including Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome are associated with LVH in newborns and children. 1, 2
These syndromic forms involve variants in genes of the RAS-MAPK signaling pathway and present with extracardiac features that distinguish them from isolated HCM. 1
Clinical Screening Recommendations for Genetic LVH
Family Screening Protocol
First-degree relatives of HCM patients require systematic clinical screening including history, physical examination, 12-lead ECG, and 2D echocardiography. 1
For children and adolescents (ages 12-18), annual evaluations are recommended due to the possibility of delayed phenotypic expression during growth periods. 1
Adult relatives with normal echocardiograms should undergo repeat clinical studies approximately every 5 years because late-onset LVH can develop even after physical maturity. 1
Genetic Testing Indications
Genetic counseling and testing should be offered when HCM is diagnosed, as identification of a pathogenic variant enables predictive testing in at-risk family members. 3
A positive genetic test in a child with borderline LV wall thickness (z-score >2 but <2.5) can establish an early diagnosis of HCM. 1
Critical Distinction: Genetic vs. Secondary LVH
The key distinguishing feature of genetic HCM is unexplained LVH in the absence of another cardiac, systemic, or metabolic disease capable of producing the observed magnitude of hypertrophy. 1
Secondary causes of LVH that must be excluded include:
Markers favoring genetic HCM over secondary LVH include: sarcomere mutations, family history of HCM, unusual or noncontiguous patterns of hypertrophy, and presence of LV outflow tract obstruction with systolic anterior motion. 1