Abstract 12163: Whole Exome Sequencing Identifies a Causative Essential Myosin Light Chain Mutation (Arg94His) in Hypertrophic Cardiomyopathy
Introduction: The essential myosin light chain (MYL3) is thought to be one of the causative genes of hypertrophic cardiomyopathy (HCM). However, clinical characteristics and long-term outcomes of MYL3 mutation carriers have still been unclear. In this study, we report a successful use of whole exome sequencing strategy as well as segregation analysis in a large HCM pedigree to identify a disease-causing MYL3 mutation. Also, we investigated clinical characteristics of HCM caused by the MYL3 gene mutation.
Methods and Results: Whole exome sequencing was performed on 7 distinct relatives from a large family with a clear HCM phenotype (5 clinically affected and 2 unaffected) (Figure A). We found 57,931 rare variants (minor allele frequency ≤0.01 or not reported in the database of 1000 Genome project), of which 162 were completely matched the segregation pattern. Manual filtering methods including a selection of deleterious variants and a removal of dbSNP-registered variants reduced the number of candidate to 1 (c.281 C>T, p.Arg94His in MYL3), which was shared in the 5 clinically affected subjects. This particular variant was also detected in 2 patients from an additional HCM family in our registry (Figure 2), thus in total 7 mutation carriers were identified. The disease-penetrance was 100%; all the 7 carriers (59 ± 19 years) exhibited asymmetrical septal hypertrophy with the substantial maximal left ventricular wall thickness of 18 ± 3 mm. Although no one suffered from cardiac death during >10 years follow-up, implantable cardioverter defibrillator was implanted in one carrier because of syncope with frequent non-sustained ventricular tachycardia.
Conclusions: A whole exome sequencing strategy with segregation analysis could be an effective diagnostic method even in a genetically heterogeneous disease as HCM. Furthermore, our study revealed that the MYL3 Arg94His mutation was associated with high disease penetrance and substantial ventricular hypertrophy.
Author Disclosures: A. Nomura: Research Grant; Modest; Yoshida Scholarship Foundation. H. Tada: None. T. Konno: None. H. Terai: None. K. Sakata: None. K. Hayashi: None. M. Kawashiri: None. N. Fujino: None. M. Yamagishi: None.
- © 2014 by American Heart Association, Inc.