Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Pathogenic Desmosome Mutations in Index-Patients Predict Outcome of Family Screening: Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Genotype-Phenotype Follow-Up Study

Article (PDF Available)inCirculation 123(23):2690-700 · June 2011with189 Reads
DOI: 10.1161/CIRCULATIONAHA.110.988287 · Source: PubMed
Abstract
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.
Bakker, Arthur A.M. Wilde, J. Peter van Tintelen and Richard N.W. Hauer
D.H. Jongbloed, Luc Jordaens, Maarten J. Cramer, Pieter A. Doevendans, Jacques M.T. de
Langen, Douwe E. Atsma, Dennis Dooijes, Arthur van den Wijngaard, Arjan C. Houweling, Jan
Maartje Noorman, Zahir A. Bhuiyan, Ans C.P. Wiesfeld, Paul G.A. Volders, Irene M. van
Moniek G.P.J. Cox, Paul A. van der Zwaag, Christian van der Werf, Jasper J. van der Smagt,
Follow-Up Study
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Genotype-Phenotype
Mutations in Index-Patients Predict Outcome of Family Screening: Dutch
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy : Pathogenic Desmosome
Print ISSN: 0009-7322. Online ISSN: 1524-4539
Copyright © 2011 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation
doi: 10.1161/CIRCULATIONAHA.110.988287
2011;123:2690-2700; originally published online May 23, 2011;Circulation.
http://circ.ahajournals.org/content/123/23/2690
World Wide Web at:
The online version of this article, along with updated information and services, is located on the
http://circ.ahajournals.org/content/suppl/2011/05/23/CIRCULATIONAHA.110.988287.DC1.html
Data Supplement (unedited) at:
http://circ.ahajournals.org//subscriptions/
is online at: Circulation Information about subscribing to Subscriptions:
http://www.lww.com/reprints
Information about reprints can be found online at: Reprints:
document. Permissions and Rights Question and Answer this process is available in the
click Request Permissions in the middle column of the Web page under Services. Further information about
Office. Once the online version of the published article for which permission is being requested is located,
can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin
Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:
at UNIVERSITEIT UTRECHT on July 9, 2012http://circ.ahajournals.org/Downloaded from
Genetics
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Pathogenic Desmosome Mutations in Index-Patients Predict Outcome of
Family Screening: Dutch Arrhythmogenic Right Ventricular
Dysplasia/Cardiomyopathy Genotype-Phenotype Follow-Up Study
Moniek G.P.J. Cox, MD, PhD*; Paul A. van der Zwaag, MD*; Christian van der Werf, MD*;
Jasper J. van der Smagt, MD; Maartje Noorman, MSc; Zahir A. Bhuiyan, MD, PhD;
Ans C.P. Wiesfeld, MD, PhD; Paul G.A. Volders, MD, PhD; Irene M. van Langen, MD, PhD;
Douwe E. Atsma, MD, PhD; Dennis Dooijes, PhD; Arthur van den Wijngaard, PhD;
Arjan C. Houweling, MD, PhD; Jan D.H. Jongbloed, PhD; Luc Jordaens, MD, PhD;
Maarten J. Cramer, MD, PhD; Pieter A. Doevendans, MD, PhD; Jacques M.T. de Bakker, PhD;
Arthur A.M. Wilde, MD, PhD; J. Peter van Tintelen, MD, PhD; Richard N.W. Hauer, MD, PhD
Background—Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant
inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5
desmosomal proteins are found in 50% of ARVD/C index patients. Previous genotype-phenotype relation studies
involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce.
Methods and Results—One hundred forty-nine ARVD/C index patients (111 male patients; age, 4913 years)
according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients;
age, 4413 years) were clinically and genetically characterized. DNA analysis comprised sequencing of
plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-
dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index
patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex
ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of
initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients
without mutation. Prolonged terminal activation duration was observed more than negative T waves in V
1
to V
3
,
especially in mutation-carrying relatives 20 years of age. In 45% of screened families, 1 affected relatives were
identified (90% with mutations).
Conclusions—Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the
majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe
amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic
mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be
identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic
relatives. (Circulation. 2011;123:2690-2700.)
Key Words: arrhythmogenic right ventricular dysplasia
cardiomyopathy
desmosome
follow-up studies
genetics
Received September 9, 2010; accepted March 14, 2011.
From the Departments of Cardiology, Medical Genetics, and Medical Physiology, University Medical Center Utrecht, Utrecht (M.G.P.J.C., J.J.v.d.S.,
M.N., D.D., M.J.C., P.A.D., J.M.T.d.B., R.N.W.H.); University Medical Center Groningen, University of Groningen, Groningen (P.A.v.d.Z., A.C.P.W.,
I.M.v.L., J.D.H.J., J.P.v.T.); Academic Medical Center Amsterdam, Amsterdam (C.v.d.W., Z.A.B., J.M.T.d.B., A.A.M.W.); Maastricht University
Medical Center, Maastricht (P.G.A.V., A.v.d.W.); University Medical Center Leiden, Leiden (D.E.A.); VU University Medical Center, Amsterdam
(A.C.H.); Erasmus Medical Center Rotterdam, Rotterdam (L.J.); Durrer Cardiogenetic Research Center, Amsterdam (J.P.v.T.); and Interuniversity
Cardiology Institute of the Netherlands, Utrecht (M.G.P.J.C., M.N., J.M.T.d.B., A.A.M.W., R.N.W.H.), the Netherlands.
*Drs Cox, van der Zwaag, and van der Werf contributed equally to this article.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.988287/DC1.
Correspondence to Moniek G.P.J. Cox, MD, PhD, Department of Cardiology, UMC Utrecht, Heidelberglaan 100, 3584CX Utrecht, Netherlands. E-mail
moniekcox@gmail.com
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.988287
2690
at UNIVERSITEIT UTRECHT on July 9, 2012http://circ.ahajournals.org/Downloaded from
A
rrhythmogenic right ventricular dysplasia/cardiomyopa-
thy (ARVD/C) is histopathologically characterized by
progressive fibrofatty replacement of myocardium, primarily
of the right ventricle (RV).
1–3
Although familial occurrence
was recognized in the first report, only in the last decade has
the genetic substrate been identified in genes encoding
desmosomal proteins.
1,4 –9
Desmosomes are protein com-
plexes in the intercalated disk, among others responsible for
mechanical coupling of cardiac myocytes. Their impairment
leads to both mechanical and electric uncoupling of cardio-
myocytes, followed by cell death with fibrofatty replace-
ment.
10 –13
Both uncoupling and altered architecture result in
activation delay, which is the pivotal mechanism for reentry
and thus ventricular tachycardia (VT).
14 –16
Editorial see p 2661
Clinical Perspective on p 2700
Arrhythmogenic right ventricular dysplasia/cardiomyopa-
thy usually shows an autosomal dominant inheritance pattern,
with incomplete penetrance and highly variable clinical
expression.
1,17–20
Classically, index patients present between
the second and fourth decades of life with VT originating
from the RV. However, sudden death can occur as early as
adolescence, whereas mutation carriers may also remain
without any signs and symptoms into old age. It has been
hypothesized that genetic modifiers could be responsible for
this phenotypic variability.
4,5,7,21–24
One of the primary clinical challenges in ARVD/C is
timely diagnosis of the concealed phase, when individuals are
at risk for arrhythmias despite the absence of symptoms. Yet,
previous studies on genotype-phenotype correlations in-
volved mainly overt ARVD/C index patients.
17–24
Follow-up
data on their relatives are scarce. Hence, the proportion of
relatives who develop signs of ARVD/C and/or (fatal) ar-
rhythmias is unknown.
Analyzing multiple genes related to ARVD/C in all index
patients is essential for both accurate diagnosis and appropri-
ate family counseling and screening. More insight into the
natural variability of the disease expression and phenotypic
consequences of genetic findings of ARVD/C is required. We
therefore sequenced all 5 desmosomal genes in 149 Dutch
ARVD/C index patients. The 302 family members were
screened for the pathogenic mutations identified in their
respective index patients. All individuals were followed up
for genotype-phenotype correlations to determine disease
penetrance and expression, including arrhythmias and sudden
death.
Methods
Patient Population
In total, 169 unrelated white Dutch index patients with ARVD/C
diagnosed according to the recently modified diagnostic Task Force
criteria (2010 TFC) or at autopsy were included.
25
An index patient
was the first member of the family diagnosed with ARVD/C in
whom DNA analysis was started. The diagnostic process included
detailed clinical and family histories, a physical examination, a
12-lead ECG, exercise testing, chest x-ray, and 2-dimensional
transthoracic echocardiography. If no VT had been recorded, 24-
hour Holter monitoring was performed. Additional magnetic reso-
nance imaging and/or left ventricular and RV cine-angiography was
performed in 118 patients (70%), and electrophysiological studies
were done in 105 patients (62%). See Table I in the online-only Data
Supplement for details on follow-up frequencies.
We also included 302 relatives of 93 index patients who under-
went cardiologic evaluation comprising at least a detailed history,
physical examination, 12-lead ECG, and 2-dimensional echocardi-
ography. If performed, outcomes of exercise tests (in 59%), 24-hour
Holter monitoring (in 66%), signal-averaged ECG (in 25%), and
electrophysiological studies (12%), as well as additional imaging by
magnetic resonance imaging and/or RV cine angiography (42%),
were included.
All 169 families received genetic counseling and consented to
both clinical evaluation according to 2010 TFC and genetic screen-
ing of ARVD/C-related genes.
25
Quantitative analyses were per-
formed at the 7 participating centers. Scoring was performed in the
core laboratory in Utrecht, the Netherlands, and patients were
inclu