title: Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy.
abstract: BACKGROUND
  The development of candidate gene approaches to enable molecular diagnosis of hypertrophic cardiomyopathy (HCM) has required extensive and prolonged efforts. Whole exome sequencing (WES) technologies have already accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. As a result, there is great interest in extending the use of WES to any of Mendelian diseases. This study investigated the potential of WES for molecular diagnosis of HCM.
  
  
  METHODS
  WES was performed on seven relatives from a large HCM family with a clear HCM phenotype (five clinically affected and two unaffected) in the Kanazawa University Hypertrophic Cardiomyopathy Registry. Serial bioinformatics filtering methods as well as using combined annotation dependent depletion (CADD) score and high heart expression (HHE) gene data were applied to detect the causative variant. Moreover, additional carriers of the variant were investigated in the HCM registry, and clinical characteristics harboring the variant were collected and evaluated.
  
  
  RESULTS
  WES detected 60020 rare variants in the large HCM family. Of those, 3439 were missense, nonsense, splice-site, or frameshift variants. After genotype-phenotype matching, 13 putative variants remained. Using CADD score and HHE gene data, the number of candidates was reduced to one, a variant in the myosin essential light chain (MYL3, NM_000258.2:c.281G>A, p.Arg94His) that was shared by the five affected subjects. Additional screening of the HCM registry (n=600) identified two more subjects with this variant. Serial assessments of the variant carriers revealed the following phenotypic characteristics: (1) disease-penetrance of 88%; (2) all clinically affected carriers exhibited asymmetric septal hypertrophy with a substantial maximum left ventricular wall thickness of 18±3mm without any obstruction.
  
  
  CONCLUSIONS
  WES combined with CADD score and HHE gene data may be useful even in HCM. Furthermore, the MYL3 Arg94His variant was associated with high disease penetrance and substantial interventricular septal hypertrophy.
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Teramoto
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Research and Education Center for Innovative and Preventive Medicine, Kanazawa University, Kanazawa, Japan. Electronic address: konnokontetsu@staff.kanazawa-u.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Konno
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hodatsu
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Won
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ino
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Fujino
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D000328:Adult; D000368:Aged; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D006352:Heart Ventricles / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018994:Myosin Light Chains / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D012042:Registries
chemical_list: D018994:Myosin Light Chains; C000609827:myosin light chain 3, human
keywords: Bioinformatics; Hypertrophic cardiomyopathy; Myosin essential light chain; Whole exome sequencing