title: Approach to family screening in arrhythmogenic right ventricular dysplasia/cardiomyopathy.
abstract: OBJECTIVE
  A combination of variable expression, age-related penetrance, and unpredictable arrhythmic events complicates management of relatives of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We aimed to (i) determine predictors of ARVD/C diagnosis and (ii) optimize arrhythmic risk stratification among first-degree relatives of ARVD/C patients.
  
  
  RESULTS
  Detailed phenotypic and outcome data of 274 first-degree relatives (46% male; 36.5 ± 18.9 years) of 138 ARVD/C probands were obtained. Ninety-six (35%) relatives were diagnosed with ARVD/C according to 2010 Task Force Criteria (TFC). Siblings had a three-fold-increased risk of ARVD/C diagnosis compared with parents and children (odds ratio 3.11, P < 0.001). Multivariable logistic regression identified symptoms (P < 0.001), being a sibling (P < 0.001), the presence of a pathogenic mutation (P < 0.001), and female sex (P = 0.010) as predictors of ARVD/C diagnosis. During 6.7 ± 3.8 years of follow-up, 21 (8%) relatives experienced a sustained ventricular arrhythmia (cycle length 271 ± 48 ms). While being a sibling was a predictor of ARVD/C diagnosis, neither relatedness to the proband (P = 0.185) nor malignant family history (P = 0.347) was significantly associated with arrhythmic events. Meeting TFC independent of family history criteria had higher prognostic value for arrhythmic events than conventional 2010 TFC, which include family history [area under the receiver operating characteristic curve 0.95 (95% CI 0.93-0.97) vs. 0.85 (95% CI 0.82-0.88), P < 0.001].
  
  
  CONCLUSIONS
  One-third of first-degree relatives develop manifest ARVD/C. Siblings have highest risk of disease, even after correcting for age and sex. Fulfilment of TFC independent of family history is superior to conventional TFC for arrhythmic risk stratification of relatives.
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Anneline S J M
authors: AS
authors: te Riele
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Cynthia A
authors: CA
authors: James
authors: Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors: Judith A
authors: JA
authors: Groeneweg
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Abhishek C
authors: AC
authors: Sawant
authors: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors: Kai
authors: K
authors: Kammers
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Brittney
authors: B
authors: Murray
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Crystal
authors: C
authors: Tichnell
authors: Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Jeroen F
authors: JF
authors: van der Heijden
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Daniel P
authors: DP
authors: Judge
authors: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Dennis
authors: D
authors: Dooijes
authors: ICIN-Netherlands Heart Institute, Utrecht, The Netherlands Department of Clinical Genetics, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
authors: J Peter
authors: JP
authors: van Tintelen
authors: Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors: Richard N W
authors: RN
authors: Hauer
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Hugh
authors: H
authors: Calkins
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA htandri1@jhmi.edu.
authors: Harikrishna
authors: H
authors: Tandri
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D042241:Early Diagnosis; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D018570:Risk Assessment; D055815:Young Adult
keywords: Arrhythmogenic right ventricular dysplasia/cardiomyopathy; Diagnosis; Family; Management; Risk stratification; Screening