Phenotypic analysis of arrhythmogenic cardiomyopathy in the Hutterite population: role of electrocardiogram in identifying high-risk desmocollin-2 carriers

J Am Heart Assoc. 2014 Dec 11;3(6):e001407. doi: 10.1161/JAHA.114.001407.

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.

Methods and 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.

Keywords: ECG screening; Hutterite population; arrhythmogenic cardiomyopathy; arrhythmogenic right ventricular cardiomyopathy/dysplasia; risk stratification; sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alberta / epidemiology
  • Arrhythmogenic Right Ventricular Dysplasia / diagnosis*
  • Arrhythmogenic Right Ventricular Dysplasia / ethnology
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Arrhythmogenic Right Ventricular Dysplasia / physiopathology
  • DNA Mutational Analysis
  • Death, Sudden, Cardiac / ethnology
  • Desmocollins / genetics*
  • Electrocardiography*
  • Ethnicity / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Homozygote
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Predictive Value of Tests
  • Prognosis
  • Retrospective Studies
  • Risk Factors
  • Stroke Volume
  • Tachycardia, Ventricular / diagnosis
  • Tachycardia, Ventricular / ethnology
  • Tachycardia, Ventricular / genetics
  • Ventricular Function, Left
  • Ventricular Function, Right
  • Ventricular Premature Complexes / diagnosis
  • Ventricular Premature Complexes / ethnology
  • Ventricular Premature Complexes / genetics
  • Young Adult

Substances

  • DSC2 protein, human
  • Desmocollins