What gene mutations are most commonly associated with left ventricular non‑compaction cardiomyopathy, and what are the recommended diagnostic and treatment approaches?

Left Ventricular Non-Compaction: Gene Mutations

Sarcomere gene mutations, particularly MYH7 and MYBPC3, are the most common genetic causes of left ventricular non-compaction (LVNC), accounting for approximately 29% of cases, with MYH7 mutations found in 13% and MYBPC3 in 8% of patients. 1

Most Common Gene Mutations

Sarcomere Genes (Account for ≥20-29% of LVNC)

• MYH7 (β-myosin heavy chain): Most frequently mutated sarcomere gene at 13% 1
• MYBPC3 (myosin-binding protein C): Second most common at 8% 1
• ZASP/LDB3 (Z-line protein): Significant contributor to isolated LVNC without congenital heart disease 1

X-Linked Mutations

• TAZ/Tafazzin gene: First identified genetic cause of isolated LVNC, responsible for Barth syndrome, presenting in male infants with heart failure, neutropenia, and 3-methylglutaconic aciduria 1

Other Important Mutations

• LMNA (lamin A/C): Associated with LVNC, conduction system disease, and high risk of sudden cardiac death even with minimal systolic dysfunction 1
• SCN5A (sodium channel gene): Causes LVNC with rhythm disturbances 1
• Dystrophin: Found in boys with Duchenne and Becker muscular dystrophies who develop LVNC 1
• Desmoplakin: Homozygous deletion causes Carvajal syndrome with LVNC, severe early-onset heart failure, woolly hair, and palmoplantar keratoderma 1

Genes Associated with Congenital Heart Disease + LVNC

• α-dystrobrevin (DTNA): Hypoplastic left heart syndrome with LVNC 1
• Nkx-2.5: LVNC with atrial septal defect 1
• MYH7: LVNC with Ebstein anomaly 1

Inheritance Patterns

Autosomal Dominant (Most Common in Adults)

• Represents 70% of inherited LVNC cases 1
• Majority of adult patients with isolated LVNC follow this pattern 1
• Reduced penetrance occurs in some families, meaning mutation carriers may not manifest disease 1

X-Linked Recessive

• Accounts for 30% of inherited LVNC 1
• Males almost exclusively affected, though rare female cases reported 1
• Primarily Barth syndrome (TAZ mutations) 1

Other Patterns

• Autosomal recessive and mitochondrial (maternal) inheritance also described 1
• Mitochondrial genome mutations identified in some cases 1

Diagnostic Yield of Genetic Testing

Genetic testing detects clinically significant variants in 35-40% of LVNC patients, with sarcomere-encoding genes being most common. 1

Testing Recommendations

• Approximately 44% of LVNC patients have inherited disease 1
• Family screening is recommended given 20-40% familial occurrence rate 2
• Patients with mutations are more likely to have major adverse cardiovascular events 2
• LV systolic dysfunction in mutation carriers confers high risk for cardiac events 2

Clinical Implications by Genotype

High-Risk Mutations Requiring Aggressive Management

• LMNA mutations: Early ICD consideration due to sudden cardiac death risk even with preserved systolic function 1
• TAZ mutations (Barth syndrome): Infants may succumb to heart failure, sudden death, or sepsis from leukocyte dysfunction 1

Neuromuscular Associations

• Dystrophin mutations: Screen for Duchenne/Becker muscular dystrophy 1
• Associated syndromes include Coffin-Lowry, Sotos, Hunter-McAlpine, and Charcot-Marie-Tooth disease 1

Treatment Approach Based on Genetics

Risk Stratification

• ICD indications follow same criteria as dilated cardiomyopathy when LVEF <40% 1
• Presence of sustained ventricular arrhythmias warrants ICD regardless of specific mutation 1
• LV non-compaction by itself is NOT an indication for ICD 1

Specific Considerations

• Increased age, LV end-diastolic diameter, symptomatic heart failure, persistent atrial fibrillation, and bundle branch block predict increased mortality 1
• Anticoagulation mandatory for atrial fibrillation, severe heart failure, previous embolism, or intracardiac thrombus 1
• Heart transplantation is definitive treatment for refractory heart failure 3

Family Screening Protocol

• Three-generation family history essential 4
• Echocardiography of first-degree relatives recommended 4
• Identify subtle forms that may have normalized spontaneously 4
• Knowledge of specific mutations affects recurrence risk counseling and clinical management 4

Common Pitfalls

• Do not assume isolated finding: LVNC frequently overlaps with dilated cardiomyopathy, apical hypertrophy, and hypertrophic cardiomyopathy 5
• Do not delay genetic testing: Genotype influences prognosis, arrhythmia risk, and family screening strategy 4
• Do not overlook extracardiac manifestations: Formal genetic evaluation mandatory when neurodevelopmental abnormalities or extracardiac malformations present 4
• Do not ignore chromosomal abnormalities: Chromosome 8p23.1 deletion and other chromosomal defects associated with LVNC 1