Published Online
on May 27, 2008

A more recent version of this article appeared on June 3, 2008

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Submitted on October 14, 2007
Accepted on March 20, 2008

Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Sabine Klaassen MD^*, Susanne Probst MSc, Erwin Oechslin MD, Brenda Gerull MD, Gregor Krings MD, Pia Schuler MD, Matthias Greutmann MD, David Hürlimann MD, Mustafa Yegitbasi MD, Lucia Pons MD, Michael Gramlich MD, Jörg-Detlef Drenckhahn MD, Arnd Heuser MD, Felix Berger MD, Rolf Jenni MD, and Ludwig Thierfelder MD

From the Max Delbrück Center for Molecular Medicine (S.K., S.P., B.G., M. Gramlich, J.-D.D., A.H., L.T.), Berlin, Germany; Clinic of Pediatric Cardiology (S.K., G.K., F.B.) and Helios Clinic Berlin-Buch (L.T.), Charité, Humboldt University of Berlin, Berlin, Germany; Adult Congenital Cardiac Centre at Peter Munk Cardiac Centre (E.O.), University Health Network/Toronto General Hospital, Toronto, Canada; Cardiovascular Center (P.S., M. Greutmann, D.H., R.J.), Division of Echocardiography, University Hospital Zürich, Zürich, Switzerland; Department of Congenital Heart Defects/Pediatric Cardiology (M.Y., F.B.), German Heart Institute, Berlin, Germany; and Ospedale Regionale di Mendrisio Beata Vergine (L.P.), Mendrisio, Switzerland.

^* To whom correspondence should be addressed. E-mail: klaassen{at}mdc-berlin.de.

Background—Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction.

Methods and Results—Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding -myosin heavy chain (MYH7), -cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in -myosin heavy chain were located mainly within the ATP binding site.

Conclusions—We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.

Key words: cardiomyopathy • genetics • heart failure • remodeling • myocardium

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