Gene mutations in apical hypertrophic cardiomyopathy

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

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2805-2811
Number of pages7
JournalCirculation
Volume112
Issue number18
DOIs
StatePublished - Nov 1 2005

Keywords

  • Cardiomyopathy
  • Genetics
  • Hypertrophy
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., & Seidman, C. E. (2005). Gene mutations in apical hypertrophic cardiomyopathy. Circulation, 112(18), 2805-2811. https://doi.org/10.1161/CIRCULATIONAHA.105.547448