Abstract 18890: An MYH7 Mutation Causes Inherited Left Ventricular Noncompaction and Sudden Death in a Large Multigenerational Family
Introduction: Mutations in MYH7, encoding the cardiac β-myosin heavy chain, cause hypertrophic (HCM) and dilated cardiomyopathy (DCM). Recently, several mutations in MYH7 were reported in patients with left ventricular noncompaction (LVNC), a rare cardiomyopathy characterized by increased trabeculation and sudden death (SCD). No large families with inherited LVNC caused by MYH7 mutations have been reported.
Methods: We identified a large family with LVNC and SCD (Pedigree). The proband is a 56 yo woman who presented at age 48 with heart failure, LVNC and a depressed ejection fraction (EF) by echocardiogram (TTE) and cardiac MRI (cMR). Medical records and blood samples were obtained from 20 adult family members, 8 clinically affected (6 LVNC; 2 DCM). DNA was isolated (PureGene), clinical genetic testing for known DCM/LVNC genes was performed on the proband’s affected daughter (GeneDx), and the mutation was identified in family members by direct sequencing. ECGs, TTEs, and cMRs were analyzed to determine PR/QRS/QTc intervals and EF; mutation carriers were compared to non-carriers in the family.
Results: A heterozygous missense mutation in a hydrophobic coil in the myosin head was identified in exon 14 of MYH7 (c.1400 T>C; p.Ile467Thr). This mutation was present in all 8 affected members, in 1 clinically unaffected obligate carrier, and in 1 symptomatic subject who had not undergone cardiac testing (penetrance ≥ 0.80). Three obligate carriers suffered SCD. Compared to noncarriers, the EF of mutation carriers was decreased (42 ± 13%, n=9, vs. 58 ±3%, n=4; p=0.03), the PR was borderline long (171 ± 33 vs. 149 ± 12 ms, n=10 each; p=0.06) and the QTc was prolonged (428 ± 32 vs. 405 ± 18 ms, n=10 each; p=0.05).
Conclusion: The Ile467Thr mutation in MYH7 causes inherited LVNC with high penetrance and SCD in a large family. Future studies are warranted to differentiate the mechanisms leading from this mutation to LVNC as contrasted with those leading from other MYH7 mutations to HCM and DCM.
Author Disclosures: G.M. Morgan: None. R. Gutmann: None. A.J. Klappa: None. X. Zhu: None. F. Ahmad: None. H. Mehdi: None. B. London: None.
- © 2014 by American Heart Association, Inc.