title: Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction.
abstract: OBJECTIVE
  Ryanodine receptor gene (RYR2) mutations are well known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, RYR2 exon 3 deletion has been identified in patients with dilated cardiomyopathy (DCM) and/or CPVT. This study aimed to screen for the RYR2 exon 3 deletion in CPVT probands, characterize its clinical pathology, and confirm the genomic rearrangement.
  
  
  RESULTS
  Our cohort consisted of 24 CPVT probands. Polymerase chain reaction (PCR)-based conventional genetic analysis did not identify any mutations in coding exons of RYR2 in these probands. They were screened using multiplex ligation-dependent probe amplification (MLPA). In probands identified with RYR2 exon 3 deletion, the precise location of the deletion was identified by quantitative PCR and direct sequencing methods. We identified two CPVT probands from unrelated families who harboured a large deletion including exon 3. The probands were 9- and 17-year-old girls. Both probands had a history of syncope related to emotional stress or exercise, exhibited bradycardia, and were diagnosed with left ventricular non-compaction (LVNC). We examined 10 family members and identified six more RYR2 exon 3 deletion carriers. In total, there were eight carriers, of which seven were diagnosed with LVNC (87.5%). Two carriers under the age of 4 years remained asymptomatic, although they were diagnosed with LVNC. Using quantitative PCR and direct sequencing, we confirmed that the deletions were 1.1 and 37.7 kb in length.
  
  
  CONCLUSIONS
  RYR2 exon 3 deletion is frequently associated with LVNC. Therefore, detection of the deletion offers a new modality for predicting the prognosis of patients with LVNC with ventricular/atrial arrhythmias, particularly in children.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Cardiovasacular Department, Saiseikai Shimonoseki General Hospital, Shimonoseki 759-6603, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Omura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Cardiovascular Department, Fukuoka Children's Hospital and Medical Center for infectious disease, Fukuoka 810-0063, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Ushinohama
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan horie@belle.shiga-med.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D001919:Bradycardia / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D018618:Echocardiography, Doppler, Color; D004562:Electrocardiography; D005091:Exons; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013575:Syncope / Q000235:genetics / Q000503:physiopathology; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000503:physiopathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Bradycardia; Catecholaminergic polymorphic ventricular tachycardia; Genetic screening; Left ventricular non-compaction; Multiplex ligation-dependent probe amplification; RYR2 exon 3 deletion