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 Mark Olson, Mitsohiro Kamisago, J. G. Seidman, Christine E. Seidman

Research output: Contribution to journalArticle

136 Citations (Scopus)

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

Fingerprint

Hypertrophic Cardiomyopathy
Sarcomeres
Mutation
Hypertrophy
Genes
Missense Mutation
Actins
Familial Hypertrophic Cardiomyopathy
Modifier Genes
Cardiomegaly
DNA Sequence Analysis
Proteins
Hemodynamics
Light

Keywords

  • Cardiomyopathy
  • Genetics
  • Hypertrophy
  • Remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

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

Gene mutations in apical hypertrophic cardiomyopathy. / Arad, Michael; Penas-Lado, Manual; Monserrat, Lorenzo; Maron, Barry J.; Sherrid, Mark; Ho, Carolyn Y.; Barr, Scott; Karim, Ahmad; Olson, Timothy Mark; Kamisago, Mitsohiro; Seidman, J. G.; Seidman, Christine E.

In: Circulation, Vol. 112, No. 18, 01.11.2005, p. 2805-2811.

Research output: Contribution to journalArticle

Arad, M, Penas-Lado, M, Monserrat, L, Maron, BJ, Sherrid, M, Ho, CY, Barr, S, Karim, A, Olson, TM, Kamisago, M, Seidman, JG & Seidman, CE 2005, 'Gene mutations in apical hypertrophic cardiomyopathy', Circulation, vol. 112, no. 18, pp. 2805-2811. https://doi.org/10.1161/CIRCULATIONAHA.105.547448
Arad M, Penas-Lado M, Monserrat L, Maron BJ, Sherrid M, Ho CY et al. Gene mutations in apical hypertrophic cardiomyopathy. Circulation. 2005 Nov 1;112(18):2805-2811. https://doi.org/10.1161/CIRCULATIONAHA.105.547448
Arad, Michael ; Penas-Lado, Manual ; Monserrat, Lorenzo ; Maron, Barry J. ; Sherrid, Mark ; Ho, Carolyn Y. ; Barr, Scott ; Karim, Ahmad ; Olson, Timothy Mark ; Kamisago, Mitsohiro ; Seidman, J. G. ; Seidman, Christine E. / Gene mutations in apical hypertrophic cardiomyopathy. In: Circulation. 2005 ; Vol. 112, No. 18. pp. 2805-2811.
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AU - Arad, Michael

AU - Penas-Lado, Manual

AU - Monserrat, Lorenzo

AU - Maron, Barry J.

AU - Sherrid, Mark

AU - Ho, Carolyn Y.

AU - Barr, Scott

AU - Karim, Ahmad

AU - Olson, Timothy Mark

AU - Kamisago, Mitsohiro

AU - Seidman, J. G.

AU - Seidman, Christine E.

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N2 - 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.

AB - 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.

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KW - Hypertrophy

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