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(Circulation. 2005;112:2805-2811.)
© 2005 American Heart Association, Inc.

Genetics

Gene Mutations in Apical Hypertrophic Cardiomyopathy

Michael Arad, MD; Manual Penas-Lado, MD; Lorenzo Monserrat, MD; Barry J. Maron, MD; Mark Sherrid, MD; Carolyn Y. Ho, MD; Scott Barr, BSc; Ahmad Karim, MD; Timothy M. Olson, MD; Mitsohiro Kamisago, MD; J.G. Seidman, PhD^*; Christine E. Seidman, MD^*

From the Department of Genetics, Harvard Medical School, Boston, Mass (M.A., S.B., M.K., J.G.S., C.E.S.); Heart Institute, Sheba Medical Center, Tel Hashomer, Israel (M.A.); Cardiology Service, Hospital Juan Canalejo, La Coruña, Spain (M.P.-L., L.M.); Minneapolis Heart Institute Foundation, Minneapolis, Minn (B.J.M.); St Luke’s Roosevelt University Hospital, New York, NY (M.S.); Division of Cardiology and Howard Hughes Medical Institute, Brigham and Women’s Hospital, Boston, Mass (C.Y.H., C.E.S.); Division of Cardiology, Wright State University, Dayton, Ohio (A.K.); Mayo Clinic Cardiovascular Genetics Laboratory, Rochester, Minn (T.M.O.); and Department of Pediatrics, Nippon Medical School, Tokyo, Japan (M.K.).

Correspondence to Christine E. Seidman, MD, Department of Genetics, NRB Room 256, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail cseidman{at}genetics.med.harvard.edu

Received March 7, 2005; revision received June 27, 2005; accepted July 19, 2005.

Background— Nonobstructive hypertrophy localized to the cardiac apex is an uncommon morphological variant of hypertrophic cardiomyopathy (HCM) that often is further distinguished by distinct giant negative T waves and a benign clinical course. The genetic relationship between HCM with typical hypertrophic morphology versus isolated apical hypertrophy is incompletely understood.

Methods and Results— Genetic cause was investigated in 15 probands with apical hypertrophy by DNA sequence analyses of 9 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2) implicated in idiopathic cardiac hypertrophy. Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in GLA, PRKAG2, or LAMP2. Clinical evaluations demonstrated familial apical HCM in 4 probands, and in 3 probands disease-causing mutations were identified. Two families shared a cardiac actin Glu101Lys missense mutation; all members of both families with clinical manifestations of HCM (n=16) had apical hypertrophy. An essential light chain missense mutation Met149Val caused apical or midventricular segment HCM in another proband and 5 family members, but 6 other affected relatives had typical HCM morphologies. No other sarcomere gene mutations identified in the remaining probands caused apical HCM in other family members.

Conclusions— Sarcomere protein gene mutations that cause apical hypertrophy rather than more common HCM morphologies reflect interactions among genetic etiology, background modifier genes, and/or hemodynamic factors. Only a limited number of sarcomere gene defects (eg, cardiac actin Glu101Lys) consistently produce apical HCM.

Key Words: hypertrophy • cardiomyopathy • genetics • remodeling

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