Mutations in the sarcomere protein gene MYH7 in Ebstein's anomaly


  • A.V. Postma
  • K. van Engelen
  • J. van de Meerakker
  • T. Rahman
  • S. Probst
  • M.J. Baars
  • U. Bauer
  • T. Pickardt
  • S.R. Sperling
  • F. Berger
  • A.F. Moorman
  • B.J. Mulder
  • L. Thierfelder
  • B. Keavney
  • J. Goodship
  • S. Klaassen


  • Circulation Cardiovascular Genetics


  • Circ Cardiovasc Genet 4 (1): 43-50


  • BACKGROUND: Ebstein's anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein's anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding beta-myosin heavy chain has been reported; here we have screened for MYH7 mutations in a cohort of probands with Ebstein's anomaly in a large population-based study. METHODS AND RESULTS: Mutational analysis in a cohort of 141 unrelated probands with Ebstein's anomaly was performed by next generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found, 5 were novel and 2 were known to cause hypertrophic cardiomyopathy (HCM). All mutations except for one 3-bp deletion were missense mutations, one was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein's anomaly (p<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of three of the probands, one of which also included another individual with Ebstein's anomaly. CONCLUSIONS: Ebstein's anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein's anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.