Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (P<0.001) and MACE (P<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (P=0.001) or chromosomal anomalies (P<0.001). MYH7 was involved in 48% of the sarcomere gene mutations. MYH7 and ACTC1 mutations had lower risk for MACE than MYBPC3 and TTN (P=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; P=0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis MYBPC3, TTN, arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients.
Keywords: diagnostics; genetics; human; left ventricular noncompaction; noncompaction cardiomyopathy; outcome.