Abstract 18890: An MYH7 Mutation Causes Inherited Left Ventricular Noncompaction and Sudden Death in a Large Multigenerational Family

Abstract

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.