title: Phenotypic analysis of arrhythmogenic cardiomyopathy in the Hutterite population: role of electrocardiogram in identifying high-risk desmocollin-2 carriers.
abstract: BACKGROUND
  The p.Gln554X mutation in desmocollin-2 (DSC2) is prevalent in ≈10% of the Hutterite population. While the homozygous mutation causes severe biventricular arrhythmogenic right ventricular cardiomyopathy, the phenotypic features and prognosis of heterozygotes remain incompletely understood.
  
  
  RESULTS
  Eleven homozygotes (mean age 32±8 years, 45% female), 28 heterozygotes (mean age 40±15 years, 50% female), and 22 mutation-negatives (mean age 43±17 years, 41% female) were examined. Diagnostic testing was performed as per the arrhythmogenic right ventricular cardiomyopathy modified Task Force Criteria. Inverted T waves in the right precordial leads on ECG were seen in all homozygotes but not in their counterparts (P<0.001). Homozygotes had higher median daily premature ventricular complex burden than did heterozygotes or mutation-negatives (1407 [IQR 1080 to 2936] versus 2 [IQR 0 to 6] versus 6 [IQR 0 to 214], P=0.0002). Ventricular tachycardia was observed in 60% of homozygotes but in none of the remaining individuals (P<0.001). On cardiac magnetic resonance imaging, homozygotes had significantly larger indexed end-diastolic volumes (right ventricular: 122±24 versus 83±17 versus 83±12 mL/m(2), P<0.0001; left ventricular: 93±18 versus 76±13 versus 80±11 mL/m(2), P=0.0124) and lower ejection fraction values compared with heterozygotes and mutation-negatives (right ventricular ejection fraction: 41±9% versus 59±9% versus 61±6%, P<0.0001; left ventricular ejection fraction: 53±8% versus 65±5% versus 64±5%, P<0.0001). Most affected individuals lacked right ventricular wall motion abnormalities. Thus, few met cardiac magnetic resonance imaging task force criteria.
  
  
  CONCLUSIONS
  The ECG reliably identifies homozygous p.Gln554X carriers and may be useful as an initial step in the screening of high-risk Hutterites. The cardiac phenotype of heterozygotes appears benign, but further prospective follow-up of their arrhythmic risk is needed.
authors.affiliation: Libin Cardiovascular Institute of Alberta & Department of Cardiac Sciences, University of Calgary, Alberta, Canada (J.A.W., H.J.D., T.Y., L.K., D.V.E., S.G.W., B.G.).
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Wong
authors.affiliation: Libin Cardiovascular Institute of Alberta & Department of Cardiac Sciences, University of Calgary, Alberta, Canada (J.A.W., H.J.D., T.Y., L.K., D.V.E., S.G.W., B.G.).
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
authors.affiliation: Libin Cardiovascular Institute of Alberta & Department of Cardiac Sciences, University of Calgary, Alberta, Canada (J.A.W., H.J.D., T.Y., L.K., D.V.E., S.G.W., B.G.).
authors.forename: Tiffany
authors.initials: T
authors.lastname: Yuen
authors.affiliation: Libin Cardiovascular Institute of Alberta & Department of Cardiac Sciences, University of Calgary, Alberta, Canada (J.A.W., H.J.D., T.Y., L.K., D.V.E., S.G.W., B.G.).
authors.forename: Louis
authors.initials: L
authors.lastname: Kolman
authors.affiliation: Libin Cardiovascular Institute of Alberta & Department of Cardiac Sciences, University of Calgary, Alberta, Canada (J.A.W., H.J.D., T.Y., L.K., D.V.E., S.G.W., B.G.).
authors.forename: Derek V
authors.initials: DV
authors.lastname: Exner
authors.affiliation: Libin Cardiovascular Institute of Alberta & Department of Cardiac Sciences, University of Calgary, Alberta, Canada (J.A.W., H.J.D., T.Y., L.K., D.V.E., S.G.W., B.G.).
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Weeks
authors.affiliation: Libin Cardiovascular Institute of Alberta & Department of Cardiac Sciences, University of Calgary, Alberta, Canada (J.A.W., H.J.D., T.Y., L.K., D.V.E., S.G.W., B.G.).
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
mesh_terms: D000293:Adolescent; D000328:Adult; D000416:Alberta / Q000453:epidemiology; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000208:ethnology; D051187:Desmocollins / Q000235:genetics*; D004562:Electrocardiography; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D013318:Stroke Volume; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics; D016277:Ventricular Function, Left; D016278:Ventricular Function, Right; D018879:Ventricular Premature Complexes / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics; D055815:Young Adult
chemical_list: C081561:DSC2 protein, human; D051187:Desmocollins
keywords: ECG screening; Hutterite population; arrhythmogenic cardiomyopathy; arrhythmogenic right ventricular cardiomyopathy/dysplasia; risk stratification; sudden cardiac death