Gene mutations in apical hypertrophic cardiomyopathy

Circulation. 2005 Nov 1;112(18):2805-11. doi: 10.1161/CIRCULATIONAHA.105.547448.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Cardiomyopathy, Hypertrophic / diagnostic imaging
  • Cardiomyopathy, Hypertrophic / genetics*
  • Carrier Proteins / genetics
  • DNA / blood
  • DNA / genetics
  • DNA / isolation & purification
  • Echocardiography
  • Female
  • Genetic Variation
  • Humans
  • Male
  • Medical Records
  • Middle Aged
  • Muscle Proteins / genetics
  • Mutation*
  • Myosin Heavy Chains / genetics
  • Retrospective Studies
  • Sarcomeres / genetics
  • Troponin T / genetics

Substances

  • Carrier Proteins
  • Muscle Proteins
  • Troponin T
  • myosin-binding protein C
  • DNA
  • Myosin Heavy Chains