Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction. Circ Cardiovasc Genet 2015 Aug;8(4):564-71
Date
06/19/2015Pubmed ID
26085007DOI
10.1161/CIRCGENETICS.115.001070Scopus ID
2-s2.0-84940035829 (requires institutional sign-in at Scopus site) 61 CitationsAbstract
BACKGROUND: The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation.
METHODS AND RESULTS: Evaluation of cardiac structure and function by echocardiography in patients with hypoplastic left heart and their first-degree relatives identified 5 individuals with right ventricular ejection fraction ≤40% after Fontan operation. Whole genome sequencing was performed on DNA from 21 family members, filtering for genetic variants with allele frequency <1% predicted to alter protein structure or expression. Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6, encoding myosin heavy chain 6, in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms. Protein modeling of the 4 highly conserved amino acid substitutions, residing in both head and tail domains, predicted perturbation of protein structure and function.
CONCLUSIONS: In contrast to dominant MYH6 mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive MYH6 mutations in patients with hypoplastic left heart and reduced systemic right ventricular ejection fraction. These findings implicate a shared molecular basis for the developmental arrest and latent myopathy of left and right ventricles, respectively.
Author List
Theis JL, Zimmermann MT, Evans JM, Eckloff BW, Wieben ED, Qureshi MY, O'Leary PW, Olson TMAuthor
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cardiac MyosinsEchocardiography
Family Health
Female
Gene Frequency
Genes, Recessive
Genetic Predisposition to Disease
Genome, Human
Heterozygote
Humans
Hypoplastic Left Heart Syndrome
Male
Models, Molecular
Mutation
Myosin Heavy Chains
Pedigree
Protein Structure, Tertiary
Sequence Analysis, DNA
Stroke Volume
