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.
Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death
