Genetic Association Between Hypoplastic Left Heart Syndrome and Cardiomyopathies

Circ Genom Precis Med. 2021 Feb;14(1):e003126. doi: 10.1161/CIRCGEN.120.003126. Epub 2020 Dec 16.


Background: Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease.

Methods: Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband and relative(s) with cardiomyopathy. Whole genome sequencing data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction.

Results: A pathogenic MYBPC3 nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular noncompaction, and 2 fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic RYR2 missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic RYR2 exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia and his father with left ventricular noncompaction and catecholaminergic polymorphic ventricular tachycardia. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in MYH6 (P=0.000068). Rare, predicted-damaging MYH6 variants were identified in 10% of probands in our cohort-4 with familial congenital heart disease, 4 with compound heterozygosity (3 with systolic ventricular dysfunction), and 4 with MYH6-FLNC synergistic heterozygosity.

Conclusions: Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation.

Keywords: cardiomyopathies; heart defects, congenital; heart failure; hypoplastic left heart syndrome; whole genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiac Myosins / genetics
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / pathology
  • Carrier Proteins / genetics
  • Case-Control Studies
  • Child
  • Codon, Nonsense
  • Female
  • Filamins / genetics
  • Genetic Predisposition to Disease*
  • Heart Failure / therapy
  • Heart Transplantation
  • Heterozygote
  • Humans
  • Hypoplastic Left Heart Syndrome / genetics*
  • Hypoplastic Left Heart Syndrome / pathology
  • Male
  • Mutation, Missense
  • Myosin Heavy Chains / genetics
  • Pedigree
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Whole Genome Sequencing


  • Carrier Proteins
  • Codon, Nonsense
  • FLNC protein, human
  • Filamins
  • MYH6 protein, human
  • RyR2 protein, human
  • Ryanodine Receptor Calcium Release Channel
  • myosin-binding protein C
  • Cardiac Myosins
  • Myosin Heavy Chains