Desmoglein-2 and desmocollin-2 mutations in dutch arrhythmogenic right ventricular dysplasia/cardiomypathy patients: results from a multicenter study.
BACKGROUND
This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 (PKP2), Desmoglein-2 (DSG2), and Desmocollin-2 (DSC2), in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We also aimed to distinguish relevant clinical and ECG parameters.


RESULTS
Clinical evaluation was performed according to the Task Force Criteria (TFC). We analyzed the genes in (a) 57 patients who fulfilled the ARVD/C TFC (TFC+), (b) 28 patients with probable ARVD/C (1 major and 1 minor, or 3 minor criteria), and (c) 31 patients with 2 minor or 1 major criteria. In the TFC+ ARVD/C group, 23 patients (40%) had PKP2 mutations, 4 (7%) had DSG2 mutations, and 1 patient (2%) carried a mutation in DSC2, whereas 1 patient (2%) had a mutation in both DSG2 and DSC2. Among the DSG2 and DSC2 mutation-positive TFC+ ARVD/C probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. In probable ARVD/C patients and those with 2 minor or 1 major criteria for ARVD/C, mutations were less frequent and they were all heterozygous. Negative T waves in the precordial leads were observed more (P<0.002) among mutation carriers than noncarriers and in particular in PKP2 mutation carriers.


CONCLUSIONS
Mutations in DSG2 and DSC2 are together less prevalent (10%) than PKP2 mutations (40%) in Dutch TFC+ ARVD/C patients. Interestingly, biallelic or digenic DSC2 and/or DSG2 mutations are frequently identified in TFC+ ARVD/C patients, suggesting that a single mutation is less likely to cause a full-blown ARVD/C phenotype. Negative T waves on ECG were prevalent among mutation carriers (P<0.002).
Bhuiyan
Zahurul A
ZA
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. z.a.Bhuiyan@amc.uva.nl
Jongbloed
Jan D H
JD
van der Smagt
Jasper
J
Lombardi
Paola M
PM
Wiesfeld
Ans C P
AC
Nelen
Marcel
M
Schouten
Meyke
M
Jongbloed
Roselie
R
Cox
Moniek G P J
MG
van Wolferen
Marleen
M
Rodriguez
Luz M
LM
van Gelder
Isabelle C
IC
Bikker
Hennie
H
Suurmeijer
Albert J H
AJ
van den Berg
Maarten P
MP
Mannens
Marcel M A M
MM
Hauer
Richard N W
RN
Wilde
Arthur A M
AA
van Tintelen
J Peter
JP
D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D051187:Desmocollins / Q000235:genetics* / Q000378:metabolism; D051301:Desmoglein 2 / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D010375:Pedigree; D051191:Plakophilins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
C081561:DSC2 protein, human; C495314:DSG2 protein, human; D051187:Desmocollins; D051301:Desmoglein 2; C495337:PKP2 protein, human; D051191:Plakophilins