Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction. (August 2015)

• Record Type: Journal Article
• Authors: Theis, Jeanne L.; Zimmermann, Michael T.; Evans, Jared M.; Eckloff, Bruce W.; Wieben, Eric D.; Qureshi, Muhammad Y.; O'Leary, Patrick W.; Olson, Timothy M.
• Is Part Of: Circulation. Volume 8:Number 4(2015)
• Publication Date: 2015-08
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.115.001070
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>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 <italic>MYH6</italic>, 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.</p> </sec> <sec> <title>Conclusions—</title> <p>In contrast to dominant <italic>MYH6</italic> mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive <italic>MYH6</italic> 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.</p> </sec> </abstract>