Shared genetic causes of cardiac hypertrophy in children and adults

Abstract

Background: The childhood onset of idiopathic cardiac hypertrophy that occurs without a family history of cardiomyopathy can portend a poor prognosis. Despite morphologic similarities to genetic cardiomyopathies of adulthood, the contribution of genetics to childhood-onset hypertrophy is unknown.

Methods: We assessed the family and medical histories of 84 children (63 boys and 21 girls) with idiopathic cardiac hypertrophy diagnosed before 15 years of age (mean [+/-SD] age, 6.99+/-6.12 years). We sequenced eight genes: MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3, MYL2, and ACTC. These genes encode sarcomere proteins that, when mutated, cause adult-onset cardiomyopathies. We also sequenced PRKAG2 and LAMP2, which encode metabolic proteins; mutations in these genes can cause early-onset ventricular hypertrophy.

Results: We identified mutations in 25 of 51 affected children without family histories of cardiomyopathy and in 21 of 33 affected children with familial cardiomyopathy. Among 11 of the 25 children with presumed sporadic disease, 4 carried new mutations and 7 inherited the mutations. Mutations occurred predominantly (in >75% of the children) in MYH7 and MYBPC3; significantly more MYBPC3 missense mutations were detected than occur in adult-onset cardiomyopathy (P<0.005). Neither hypertrophic severity nor contractile function correlated with familial or genetic status. Cardiac transplantation and sudden death were more prevalent among mutation-positive than among mutation-negative children; implantable cardioverter-defibrillators were more frequent (P=0.007) in children with family histories that were positive for the mutation.

Conclusions: Genetic causes account for about half of presumed sporadic cases and nearly two thirds of familial cases of childhood-onset hypertrophy. Childhood-onset hypertrophy should prompt genetic analyses and family evaluations.

Figure 1. Echocardiogram Showing Unexplained Asymmetric Left Ventricular Hypertrophy Diagnosed in the First Week of Life during Evaluation of a Boy for Aspiration Pneumonia

The interventricular septum (IVS) measured 12 mm, and the posterior wall (PW) measured 7 mm. The ejection fraction was 75%, and the calculated left ventricular mass was 41 g. Genetic analyses revealed a previously unreported missense mutation, MYBPC3 Arg495Gly; other amino acid substitutions at this codon are known causes of hypertrophic cardiomyopathy. Ao denotes aorta, LA left atrium, and RV right ventricle.

Figure 2. Family Pedigrees of 11 Patients with Childhood-Onset Idiopathic Cardiac Hypertrophy and No Family History of Cardiomyopathy

Mutations identified in patients (arrows) were studied in family members, and their clinical status was ascertained. The plus symbol denotes the presence of the mutation, the minus symbol the absence of the mutation, and NA mutation status not available. Four mutations that were not detected in parents were new, and seven mutations were inherited from one parent. Circles denote female family members, squares male family members, solid symbols clinically affected family members, open symbols clinically unaffected members, and blue symbols family members with unknown clinical status.