University of Groningen
The value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy
Netherlands ACM Registry; de Brouwer, Remco; Bosman, Laurens P; Gripenstedt, Sophia;
Wilde, Arthur A M; van den Berg, Maarten P; van Tintelen, J Peter; de Boer, Rudolf A; Te Riele, Anneline S J M
Published in:
Heart Rhythm
DOI:
10.1016/j.hrthm.2022.05.038
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
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Publication date:
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Citation for published version (APA):
Netherlands ACM Registry, de Brouwer, R., Bosman, L. P., Gripenstedt, S., Wilde, A. A. M., van den Berg, M. P., van Tintelen, J. P., de Boer, R. A., & Te Riele, A. S. J. M. (2022). The value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm.
https://doi.org/10.1016/j.hrthm.2022.05.038
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The value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy
Remco de Brouwer, MD, Laurens P. Bosman, MD, Sophia Gripenstedt, BSc, Arthur A.M. Wilde, MD PhD, Maarten P. van den Berg, MD PhD, J. Peter van Tintelen, MD PhD, Rudolf A. de Boer, MD PhD, Anneline S.J.M. te Riele, MD PhD, on behalf of the Netherlands ACM Registry
PII: S1547-5271(22)02055-0
DOI: https://doi.org/10.1016/j.hrthm.2022.05.038 Reference: HRTHM 9435
To appear in: Heart Rhythm
Received Date: 21 March 2022 Revised Date: 13 May 2022 Accepted Date: 20 May 2022
Please cite this article as: de Brouwer R, Bosman LP, Gripenstedt S, Wilde AAM, van den Berg MP, van Tintelen JP, de Boer RA, te Riele ASJM, on behalf of the Netherlands ACM Registry, The value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy, Heart Rhythm (2022), doi: https://doi.org/10.1016/j.hrthm.2022.05.038.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2022 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
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Title: The value of genetic testing in the diagnosis and risk stratification
1
of arrhythmogenic right ventricular cardiomyopathy
2
Running title: The value of genetic testing in ARVC
3
Authors: Remco de Brouwer, MDa,b, Laurens P. Bosman, MDb,c, Sophia Gripenstedt, BScc, Arthur A.M.
4
Wilde, MD PhDe, Maarten P. van den Berg, MD PhDa, J. Peter van Tintelen, MD PhDd,Rudolf A. de Boer, 5
MD PhDa, Anneline S.J.M. te Riele, MD PhDb,c, on behalf of the Netherlands ACM Registry.
6
Affiliations:
7
a. Department of Cardiology, University Medical Center Groningen, University of Groningen, 8
Groningen, the Netherlands 9
b. Netherlands Heart Institute, Utrecht, the Netherlands 10
c. Department of Cardiology, University Medical Center Utrecht*, University of Utrecht, Utrecht, 11
the Netherlands 12
d. Department of Genetics, University Medical Center Utrecht*, University of Utrecht, Utrecht, the 13
Netherlands 14
e. Department of Cardiology, Amsterdam University Medical Center*, University of Amsterdam, 15
Amsterdam, the Netherlands 16
*University Medical Center Utrecht and Amsterdam University Medical Center are members of the 17
European Reference Network for rare, low prevalence and complex heart diseases: ERN GUARD-Heart 18
Corresponding author: R. de Brouwer, r.de.brouwer@umcg.nl, Hanzeplein 1, Building 3215, room 419, 19
internal code AB43, 9713 GZ, Groningen, the Netherlands.
20
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2 The authors have no conflicts of interest to disclose.
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Word count: 5320 22
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Abstract
23
Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by risk of 24
malignant ventricular arrhythmias (VA). ARVC is diagnosed using an array of clinical tests in the 25
consensus-based task force criteria (TFC), one of which is genetic testing.
26
Objective: To investigate the value of genetic testing in diagnosing ARVC and its relation to the 27
occurrence of first malignant VA.
28
Methods: A multicenter cohort of ARVC patients was scored using the revised 2010 TFC with and 29
without genetic criterion, analyzing any resulting loss or delay of diagnosis. Malignant VA was defined as 30
sustained ventricular arrhythmia (≥30s duration at ≥100 bpm or requiring intervention).
31
Results: We included 402 subjects (55% male, 54% proband, 40 [27-51] years old at presentation) who 32
were diagnosed with definite ARVC. A total of 232 (58%) subjects fulfilled genetic testing criteria.
33
Removing the genetic criterion caused loss of diagnosis in 18 (4%) patients (11/216 [5%] probands, 34
7/186 [4%] relatives), and delay of diagnosis ≥30 days in 22 (5%) patients (21/216 [10%] probands, 1/186 35
[0.5%] relative). A first malignant VA occurred in no patients who lost diagnosis and in 3 patients (3/216 36
[1%] probands and no relatives) during their diagnosis delay, none fatal. Time to event analysis showed 37
no significant difference in time from diagnosis to malignant VA between pathogenic variant carriers and 38
non-carriers.
39
Conclusion: Disregarding the genetic criterion of the TFC caused loss or delay of diagnosis in 10%
40
(n=40/402) of ARVC patients. Malignant VA occurred in 1% (n=3/402) of cases with lost or delayed 41
diagnosis, none fatal.
42
Keywords: ARVC, ACM, arrhythmogenic right ventricular dysplasia/cardiomyopathy, screening, 43
diagnosis, prognosis, efficacy, Task Force Criteria 44
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Introduction
45
Arrhythmogenic right ventricular cardiomyopathy (ARVC), the right dominant subform of 46
arrhythmogenic cardiomyopathy (ACM), is characterized by fibrofatty replacement of cardiomyocytes 47
leading to ventricular dysfunction and an increased risk of malignant ventricular arrhythmias (MVA).1,2 48
The clinical gold standard for ARVC diagnosis is the revised 2010 Task Force Criteria (TFC).1 These TFC 49
consist of electrocardiographic characteristics (depolarization and repolarization abnormalities), tissue 50
characterization, imaging (echocardiographic and cardiac magnetic resonance imaging (CMR)) 51
abnormalities, as well as arrhythmic features and family history.
52
ARVC is often familial with incomplete penetrance and variable expressivity. Genetic causes underlying 53
disease have mainly been identified in genes encoding proteins of the cardiac desmosome. As a result, 54
genetic testing for pathogenic desmosomal variants is regularly performed. In contrast to other diseases, 55
these genetic testing results are part of the diagnostic criteria; i.e. the presence of a (likely) pathogenic 56
variant in an ARVC-related gene is considered a major criterion for ARVC diagnosis. Of note, the 57
presence of either 2 major or 1 major and 2 minor of 4 minor criteria is sufficient for a definite ARVC 58
diagnosis, underscoring the importance of genetics in clinical diagnosis in the 2010 TFC framework. To 59
complicate matters even further, determining pathogenicity of a genetic variant is challenging, and is 60
based upon criteria proposed by the American College of Medical Genetics and Genomics/Association 61
for Molecular Pathology (ACMG/AMP). Indeed, a recent study showed that nearly 40% of variants 62
believed to underlie ARVC were mis-classified3. This misclassification may easily lead to a misdiagnosis of 63
ARVC by lowering the scoring threshold to reach a diagnosis. As such, previous studies4–6 have suggested 64
that assigning the genetic criterion as a major criterion could result in overdiagnosis and its relative 65
weight in the TFC may have to be reconsidered.7,8 However, objective studies that evaluate the 66
diagnostic value of the genetic testing criterion in the 2010 TFC are lacking. Leveraging a large 67
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multicenter cohort containing relatives of ARVC proband patients, the aim of this study was to 68
determine the incremental value of the genetics TFC criterion for ARVC diagnosis and risk assessment.
69
Materials and Methods
70
Study Population
71
The study population was recruited from the Netherlands Arrhythmogenic Cardiomyopathy Registry 72
(ACM Registry; www.acmregistry.nl), Figure 1.9 This registry contains records from all seven university 73
medical centers in the Netherlands, minimizing center-based bias.All participants provided informed 74
consent for research at the time of genetic testing. The Institutional Review Board approved the 75
protocol and the registry is recorded in the Netherlands Trial Registry, project 7097 76
(www.trialregister.nl). The study was performed in line with the principles of the Helsinki Declaration as 77
revised in 2013.
78
Clinical evaluation
79
Patients were evaluated as described previously9. We used clinical data derived from anonymized 80
medical records. Demographics, medical and family history, electrocardiographs (ECGs), exercise stress 81
tests, Holter registrations, signal-averaged ECGs, echocardiograms, CMR scans, electrophysiological 82
studies, biopsies, genetic tests, and pathology reports were collected.
83
ARVC diagnosis
84
A definite ARVC diagnosis was ascertained using the aforementioned 2010 TFC1,10 which evaluates six 85
categories, each containing major (2 points) and minor (1 point) criteria. A total of at least 4 points from 86
different categories is required for a definite diagnosis of ARVC. Notably, apart from a positive genetic 87
testing result, a patient may also score points for family history for example if they have a relative with 88
ARVC in the absence of a currently known (likely) pathogenic variant, as specified below.
89
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Genetic testing and family history evaluation
90
As per current guidelines, all ARVC probands were offered genetic testing for ARVC-related genes, while 91
relatives were solely tested for the variant identified in the proband. Genetic test results were acquired 92
from the years 2002-2021 and consisted of next generation sequencing (NGS) panels, Sanger 93
sequencing, and multiplex-ligation dependent probe amplification; a list of tested genes included in 94
these NGS panels can be found in Supplementary Table 1. Genetic testing results were re-adjudicated as 95
per ACMG/AMP guidelines where class 4 (likely pathogenic, LP) and class 5 (pathogenic, P) variants were 96
classified as likely causative for disease. Of note, genetic testing was only considered positive (i.e. major 97
Task Force Criteria were only fulfilled) if a (likely) pathogenic variant was found in a gene with definite 98
evidence for ARVC causation (i.e. PKP2, DSP, DSG, DSC2, JUP and TMEM43), as specified by the Clinical 99
Genome Resource.11 Consequently, the Dutch founder variant in the PLN gene (p.Arg14del) was not 100
considered as an ARVC-related gene for the purpose of the present analysis.
101
Family history was evaluated by cardiogenetic counselors with particular interest in ARVC. As in previous 102
ARVC studies4,12–14, probands were defined as the first member of a family to be diagnosed with ARVC 103
and in whom genetic testing started. The current TFC lists the following family history criteria: confirmed 104
ARVC in a first-degree relative according to the TFC, ARVC confirmed pathologically in a first-degree 105
relative, and identification of a (likely) pathogenic mutation in the subject themselves as major criteria;
106
and unconfirmed ARVC in a first-degree relative, premature sudden death (<35 years old) due to 107
suspected ARVC in a first-degree relative, and confirmed ARVC in a second-degree relative as minor 108
criteria.
109
Outcomes
110
We collected data on the occurrence of malignant ventricular arrhythmia (MVA), which was defined as 111
sudden cardiac death, resuscitated sudden cardiac arrest, spontaneous sustained ventricular tachycardia 112
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(VT) or appropriate implantable cardioverter-defibrillator (ICD)-intervention. Definitions were used as 113
described previously15. 114
Statistical analyses
115
Continuous data were presented as means ± standard deviations (SD) or as medians with interquartile 116
ranges [IQR], as appropriate. Categorical variables were presented as absolute values followed by 117
percentages. Variables were compared using the chi-square test for categorical variables, the Student t- 118
test for normally distributed continuous variables, and the Mann-Whitney-U test for non-normally 119
distributed continuous variables. Univariable and multivariable analysis was performed to investigate 120
potential risk factors for MVA occurrence. We plotted survival curves stratified by genetic testing results 121
in order to analyze the occurrence of MVA over time. Start time was set at the date of ARVC diagnosis 122
and end time at the date of last follow up or first MVA. Non-parametric survival analysis was performed 123
using Kaplan-Meier estimation. The resulting survival functions were tested for significance using the 124
log-rank test.16 Analyses were performed using R-Studio version 1.3.1073, a graphical interface for the R 125
statistical package, version 4.0.2. P-values < 0.05 were considered statistically significant.
126
Results
127
Study population 128
As of February, 2022, the Netherlands ACM Registry contained data from 2052 ARVC patients (516 129
probands and 1536 relatives). From this initial cohort, 402 subjects (216 probands and 186 relatives) 130
fulfilled definite ARVC criteria. Patient characteristics are shown in Table 1. Overall, 55% (n=221) of 131
these patients were male, with a median age of 40 [27-51] years at presentation. Compared to relatives, 132
probands were significantly more often male (p<0.001). There was no significant difference in age at 133
first clinical presentation. Not surprisingly, probands had more TFC points than relatives with a median 134
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of 6 [5-8] vs. 5 [4-6] points, p<0.001. Genetic testing results revealed a (likely) pathogenic ARVC- 135
associated variant in 232 (58%) subjects, most commonly in the Plakophilin-2 gene (n=211, 52%), 136
followed by Desmoplakin (n=15, 4%), Desmoglein (n=6, 2%) and Desmocollin (n=6, 2%), see Table 1.
137
Family history evaluation 138
Table 2 shows the distribution of family history criteria in the study population. Overall, 290 (72%) 139
subjects (124 [57%] probands and 166 [89%] relatives) fulfilled major family history criteria, while 86 140
(21%) subjects (18 [8%] probands and 68 [27%] relatives) fulfilled minor family history criteria. Non- 141
genetic family history criteria were fulfilled in 29 (13%) of probands and 169 (91%) of relatives; the 142
remaining 17 (9%) relatives without non-genetic family history criteria were distant family members of 143
ARVC patients and hence did not fulfill non-genetics TFC in the family history category.
144
Role of genetic testing in clinical diagnosis of probands 145
Out of 216 included probands, 121 (56%) harbored a (likely) pathogenic ARVC-related variant. Removing 146
genetic testing from the TFC led to a total of 11 (5%) probands who lost their diagnosis and 21 (10%) 147
probands who had their diagnosis delayed by 30 days or more (range 38 days-35 years). More 148
information on the presentation and clinical course of these subjects can be found in Supplementary 149
Tables 2 and 3. None of the probands lost their diagnosis upon removing the non-genetic family history 150
criterion group.
151
Probands were followed over 13 [7-20] years. Of the 11 (5%) probands who would have been missed if 152
genetic testing was disregarded, none experienced MVA and all were still alive at last follow-up. Of the 153
21 (10%) probands with a diagnosis delay should genetic testing be disregarded, three (1%) probands 154
experienced MVA during that delay, all of whom were alive at last date of follow-up.
155
156
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9 Role of genetic testing in clinical diagnosis of relatives 157
Out of 186 included relatives, 111 (60%) harbored a (likely) pathogenic ARVC-related variant. Removing 158
genetic testing from the TFC led to a total of seven (4%) relatives who lost their diagnosis and one (0.5%) 159
relative who had their diagnosis delayed by 30 days or more (72 days). More information on the 160
presentation and clinical course of these subjects can be found in Supplementary Tables 2 and 3. In 161
addition, 38 (20%) relatives lost their diagnosis upon removing the non-genetic family history criterion 162
group.
163
Relatives were followed over 10 [6-15] years. Of the seven (4%) relatives who would have been missed if 164
genetic testing was disregarded, none experienced a MVA and all were alive at the time of last follow- 165
up. The one (0.5%) relative with a diagnosis delay should genetic testing be disregarded did not 166
experience MVA during or after that delay and was still alive at last follow-up.
167
Association of genetic testing with outcome 168
A definite disease diagnosis is typically regarded as a prerequisite for subsequent arrhythmic events in 169
ARVC patients4,17. As such, risk stratification efforts typically starts with a definite ARVC diagnosis15. 170
However, our data demonstrate that date of diagnosis may be delayed if genetic testing is disregarded 171
as diagnostic criterion. We therefore believe it is important to evaluate how date of diagnosis relates to 172
development of subsequent MVA in these patients.
173
Since ARVC diagnosis cannot be ascertained if an individual has not yet come to medical attention, 174
further analyses were restricted to those who did not present with sustained ventricular arrhythmia or 175
equivalent event and in whom outcomes could be ascertained. We will refer to this group as the primary 176
prevention cohort.
177
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Among 238 primary prevention ARVC patients in our cohort, 61 (26%) experienced a first MVA during 11 178
[7-16] years of follow-up. Those who experienced MVA were 41 (67%) male, with an age at first 179
presentation of 36 [29-45] years. The mean time between diagnosis and MVA was 3 [1-8] years.
180
Table 3 and Figure 2 show predictors of the occurrence of a first MVA among primary prevention ARVC 181
patients. As can be observed in Figure 2, there was no significant difference in the time from confirmed 182
ARVC diagnosis to a first MVA between carriers of a pathogenic variant and non-carriers. Table 3 shows 183
that male sex and proband status were significant risk factors for the occurrence of MVA, while carrying 184
a pathological genetic variant was not.
185
Discussion
186
The last decade has witnessed the identification of pathogenic variants associated with ARVC, and 187
genetic testing for ARVC-related variants is now routinely performed. Different from all other forms of 188
cardiomyopathy, these genetic testing results are an integral part of the diagnostic criteria for ARVC, 189
counting as a major criterion towards ARVC diagnosis. Despite the relative importance of genetic testing 190
in diagnosing ARVC, the TFC framework does not specify which genes should be considered disease- 191
causing, and determining pathogenicity of variants is challenging in the context of the background 192
“genetic noise” (i.e. presence of pathogenic variants in the healthy population)7,18. Our results show that 193
removal of genetic testing from the 2010 TFC scoring system causes loss or delay of diagnosis in 10% (40 194
out of 402) of ARVC patients. While this is a sizable number, the number of subjects who experience a 195
potential fatal outcome (MVA) during that delay is small (<1%, 3 out of 402). Likewise, the presence of a 196
pathogenic variant was not significantly associated with MVA during follow-up.
197
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History of the TFC
198
Since there is no single gold standard for ARVC diagnosis, a multitude of clinical tests is required to 199
determine a definite ARVC diagnosis. The resulting “Task Force Criteria” were first described in 1994, 200
and revised in 2010 to increase sensitivity for early disease . Of note, the revised TFC included genetic 201
testing as major diagnostic criterium, together with other new diagnostic criteria (e.g. the presence of 202
prolonged terminal activation duration and quantitative cutoffs for imaging tests). The combined 203
additional value of these revised criteria was tested through post-hoc analysis in a cohort of 108 204
probands, but a focused analysis on the performance of the genetics criterion to this framework is 205
lacking. Recently, Bosman et al. showed a limited value of genetic and family history criteria within the 206
TFC framework, while arrhythmic and electrocardiographic criteria provided 100% sensitivity in their 207
cohort6. This suggests that not all TFC can be considered equal and that a critical appraisal of the true 208
diagnostic value of these criteria is warranted.
209
The value of genetic testing for diagnosis
210
Our study shows that 10% of definite ARVC patients have loss or >30 days delay of diagnosis upon 211
removal of genetic testing from the TFC framework. Of note, probands had greater reliance on genetics 212
criteria than relatives, which is understandable as relatives (by definition) fulfill other non-genetic family 213
history criteria for ARVC.
214
The disappointing diagnostic value of genetic testing criteria can be explained by the incomplete 215
penetrance of ARVC: simply carrying a pathogenic variant which can cause ARVC does not equal 216
developing the cardiomyopathy itself. In addition, penetrance among relatives is known to be age- 217
dependent, and only a third of relatives will develop ARVC.19 This is in sharp contrast to population- 218
based cohorts, where penetrance of ARVC-related variants is estimated to be well under 10%13,20. As 219
such, one may conclude that a positive genetic test result may contribute to overdiagnosis of ARVC by 220
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lowering the scoring threshold to reach a diagnosis by half. While this lower threshold may be helpful 221
for early detection of disease among at-risk family members, these early diagnoses should be balanced 222
against the risk of misdiagnosis should pathogenicity of the variants be incorrectly classified, and against 223
the psychosocial impact of reaching a definite diagnosis among those who may never experience any 224
adverse clinical events. This study was not designed to evaluate either one of these outcomes. However, 225
a focused analysis on the relationship between genetic testing results and MVA may shed light on the 226
clinical value of genetic testing results in the management of ARVC patients.
227
The value of genetic testing for risk stratification
228
The results of our study show that MVA does not occur in any of the patients who rely on genetic testing 229
for ARVC diagnosis, and in only a minority of probands during their diagnosis delay should genetic 230
testing be disregarded. Of note, none of these MVAs were lethal. Likewise, the presence of a pathogenic 231
variant was not significantly associated with MVA among primary prevention ARVC patients in our 232
cohort.
233
Our results are in line with previous studies that evaluated the value of genetic testing for ARVC risk 234
stratification. In a cohort of 274 first-degree relatives of ARVC probands4, all subjects who experienced 235
ventricular arrhythmias had phenotypic expression of disease and hence fulfilled TFC independent of 236
family history. Similarly, Zorzi et al. showed that an overt disease phenotype was a prerequisite for 237
ventricular arrhythmias in ARVC patients17. Genetic testing was also evaluated as prognostic marker in a 238
multicenter “risk calculator” for ventricular arrhythmias15,21, where genetic testing was not significantly 239
associated with arrhythmic events and fell out of the model. While this finding was replicated in other 240
cohorts, the presence of multiple genetic variants was significantly associated with worse outcome in 241
ARVC patients22. In addition, a genotype-specific risk model was previously published for 242
phospholamban cardiomyopathy23, a disease that associates with both an arrhythmogenic and dilated 243
cardiomyopathy phenotype. It would be interesting to compare the available risk models to provide 244
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further guidance on the optimal approach to personalized (and perhaps genotype-specific) risk 245
stratification.
246
Clinical implications
247
According to general recommendations for genetic testing in inherited cardiomyopathies24, genotyping 248
is indicated in a proband who already fulfills diagnostic criteria for ARVC, and may be considered in 249
those with borderline phenotypic manifestations, provided that the results are interpreted by experts in 250
the field of molecular genetics who have experience with ARVC. In line with these recommendations, we 251
believe that the identification of a likely pathogenic or pathogenic (LP/P) variant is of great importance 252
for cascade genetic screening in relatives, family planning, and genotype-phenotype associations (e.g.
253
the finding that multiple pathogenic variants are associated with malignant outcomes) for the treating 254
cardiologist.
255
The role of genetic testing in ARVC diagnosis may be less clear. In this context, one should take the 256
incomplete penetrance and variable expressivity of this disease into account: the presence of a 257
pathogenic variant will already lead an individual halfway towards the diagnosis, while only one in three 258
variant carriers will actually develop disease and one in ten relatives develop arrhythmias4. Hence, while 259
inclusion of genetic testing in the TFC leads to greater sensitivity for early disease, this may come at the 260
expense of (psychosocial and/or therapeutic) consequences to subjects who will never develop adverse 261
outcome among 1) those who have mild phenotypic ARVC expression; and 2) those in whom genetic 262
testing results are misinterpreted and a different disease is at play. We therefore believe that the 263
presence of a pathogenic ARVC-related variant may be more strongly related to the a priori risk of 264
developing ARVC, rather than actually being diagnostic for the disease. The median time from ARVC 265
diagnosis (by conventional TFC, i.e. with genetic testing included) to ventricular arrhythmia in our cohort 266
was 3 [1-8] years. This is important, as this is the time during which clinicians are able to intervene in 267
order to prevent arrhythmias or manage disease progression, e.g. by implementing preventative 268
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measures such as exercise restriction. Since disregarding genetic testing results only slightly delayed this 269
interval and no lethal events occurred among missed or delayed diagnoses, removal of genotyping from 270
the TFC does not seem to significantly impact clinical outcome. Of note, the impact of a loss of diagnosis 271
in probands on their respective at-risk families remains uncertain. Future studies should confirm these 272
findings, and further evaluate the pros (i.e. yield of early diagnosis and the ability to implement 273
preventative measures such as exercise restriction) and cons (i.e. repercussions among overdiagnosed 274
and misdiagnosed patients) of genetic testing within the TFC framework.
275
Limitations
276
While the multicenter origin of our data helps mitigate center-based bias, data is typically collected 277
retrospectively which may have led to selection bias. Additionally, our registry contains mainly Western 278
European ethnicities and thus results may not be directly extrapolated to other ethnicities. The delay in 279
reaching a definite diagnosis by excluding genetic testing has a wide span ranging from 38 days to 35 280
years. This may reflect the wide degree of disease progression, a detailed evaluation of which remains 281
beyond the scope of the present manuscript. It should be stressed that the potential loss of diagnosis in 282
a proband may have potentially detrimental consequences in their respective relatives, who may not be 283
evaluated and whose disease may go unnoticed.
284
Conclusions
285
Removing genetic testing from the 2010 TFC leads to lost or delayed ARVC diagnosis in 10% of definite 286
ARVC patients. A minority (1%) of these patients experienced potentially life-threatening ventricular 287
arrhythmia during this delay. Moreover, genetic testing results were not associated with ventricular 288
arrhythmias among primary prevention ARVC patients. These results will be of value for clinicians caring 289
for these patients and their family members.
290
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Acknowledgements
291
On behalf of the Netherlands ACM Registry collaborators: A.F. Baas (UMC Utrecht, Department of 292
Medical Genetics, Utrecht, The Netherlands); D.Q.C.M. Barge-Schaapveld (LUMC, Department of Clinical 293
Genetics, Leiden, The Netherlands); S.M. Boekholdt (Amsterdam UMC, Heart Center, Department of 294
Clinical and Experimental Cardiology, Amsterdam, The Netherlands); M. Bourfiss (UMC Utrecht, 295
Department of Cardiology, University of Utrecht, Utrecht, The Netherlands); M.J.M. Cramer (UMC 296
Utrecht, Department of Cardiology, University of Utrecht, Utrecht, The Netherlands); D. Dooijes (UMC 297
Utrecht, Department of Genetics, Utrecht University, Utrecht, The Netherlands); J.A. Groeneweg (UMC 298
Utrecht, Department of Cardiology, University of Utrecht, Utrecht, The Netherlands); J.D.H. Jongbloed 299
(UMC Groningen, Department of Genetics, Groningen, The Netherlands); F. van Lint (UMC Utrecht, 300
Department of Cardiology, University of Utrecht, Utrecht, The Netherlands); K.P. Loh (UMC Utrecht, 301
Department of Cardiology, University of Utrecht, Utrecht, The Netherlands); R.N. Planken (Amsterdam 302
UMC, AMC, Department of Radiology and Nuclear Medicine, Amsterdam, The Netherlands); N.H.J.
303
Prakken (UMC Groningen, Department of Radiology, Groningen, The Netherlands); J.J. van der Smagt 304
(UMC Utrecht, Department of Genetics, Utrecht University, Utrecht, The Netherlands); A.J. Teske (UMC 305
Utrecht, Department of Cardiology, University of Utrecht, Utrecht, The Netherlands); T.E. Verstraelen 306
(Amsterdam UMC, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam, The 307
Netherlands); T.A.B. van Veen (UMC Utrecht, Department of Medical Physiology, University of Utrecht, 308
Utrecht, The Netherlands); B.K. Velthuis (UMC Utrecht, Department of Radiology, University of Utrecht, 309
Utrecht, The Netherlands); A. Vink (UMC Utrecht, Department of Pathology, University of Utrecht, 310
Utrecht, The Netherlands); A.C. van der Wal (Amsterdam UMC, AMC, Department of Pathology, 311
Amsterdam, The Netherlands); S.C. Yap (Erasmus MC, Department of Cardiology, Rotterdam, The 312
Netherlands); K. Zeppenfeld (LUMC, Department of Cardiology, Leiden, the Netherlands).
313
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Funding sources
314
The work was financially supported by the Netherlands Cardiovascular Research Initiative, an initiative 315
supported by the Dutch Heart Foundation (CardioVasculair Onderzoek Nederland (CVON) projects:
316
PREDICT2 2018-30, eDETECT 2015-12). Additional financial support was received from CURE-PLaN, a 317
network funded by the Leducq Foundation.
318
References
319
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Tables
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Table 1: Characteristics of total cohort 399
*Major criteria = 2 points; minor criteria = 1 points. †: Only genetic variants related to ARVC determined as 400
pathogenic/likely pathogenic in the following genes: PKP2, DSP, JUP, DSG2, DSC2, and TMEM43. Of note, a total of 401
90 patients (42 probands, 48 relatives) harbored the PLN p.Arg14del founder variant, which was not counted as an 402
ARVC-related gene for the purpose of the present analysis. ‡: Insufficient group size for meaningful statistical 403
comparison.
404
Overall (N=402) Proband (N=216) Relative (N=186) p-value Age at presentation, years [IQR] 40 [27-51] 40 [29-49] 40 [24-51] 0.487
Male sex, n (%) 221 (55) 145 (67) 76 (41) < 0.001
Pathogenic variant†, n (%) 232 (58) 121 (56) 111 (60) 0.523
PKP2, n (%) 211 (52) 105 (49) 106 (57) 1.000
DSP, n (%) 15 (4) 11 (5) 4 (2) NA‡
DSG2, n (%) 6 (2) 4 (2) 2 (1) NA‡
DSC2, n (%) 6 (2) 3 (2) 3 (2) NA‡
TFC points [IQR] 6 [4-7] 6 [5-8] 5 [4-6] < 0.001
Repolarization criteria [IQR]* 2 [1-2] 2 [1-2] 1 [0-2] < 0.001
Depolarization critera [IQR]* 1 [0-1] 1 [0-1] 1 [0-1] 0.307
Arrhythmia criteria [IQR]* 1 [1-2] 1 [1-2] 1 [0-1] < 0.001
Tissue criteria [IQR]* 0 [0-0] 0 [0-0] 0 [0-0] 0.001
Imaging criteria [IQR]* 2 [0-2] 2 [0-2] 1 [0-2] < 0.001
Follow-up duration, years 11 [6-17] 13 [7-20] 10 [6-15] < 0.001
Malignant ventricular arrhythmia, n (%) 202 (50)
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158 (73) 44 (24) < 0.00121 Table 2: Distribution of family history criteria
405
406
407
Table 3: Univariable and multivariable analysis of potential factors influencing the risk of malignant ventricular 408
arrhythmia.
409
Univariable Multivariable
Hazard ratio (95% CI) p-value Hazard ratio (95% CI) p-value Age at presentation 0.99 (0.98-1.01) 0.508 0.99 (0.97-1.01) 0.329 Male sex 3.35 (1.85-6.23) < 0.001 3.03 (1.64-5.19) < 0.001 Relative status 0.30 (0.17-0.55) < 0.001 0.31 (0.17-0.58) < 0.001 Pathogenic variant 1.38 (0.77-2.51) 0.284 1.50 (0.80-2.88) 0.212 410
Overall (N=402) Proband (N=216) Relative (N=186)
Any major family history criterium, n (%) 290 (72) 124 (57) 166 (89)
Genetic testing positive, n (%) 232 (58) 121 (56) 111 (60)
First degree relative with ARVC, n (%) 151 (38) 11 (5) 140 (75)
First degree relative with ARVC (autopsy), n (%) 26 (6) 4 (2) 22 (12)
Any minor family history criterium, n (%) 86 (21) 18 (8) 68 (37)
First degree relative with uncertain ARVC diagnosis, n (%) 8 (2) 2 (<1) 6 (3) SCD (<35 years) due to suspected ARVC, n (%) 33 (8) 14 (6) 19 (10)
Second degree relative with ARVC, n (%) 50 (12) 2 (<1) 48 (26)
Any non-genetic family history criterium, n (%) 198 (49) 29 (13) 169 (78)
Loss of diagnosis with genetic criterion removed, n (%) 18 (4) 11 (5) 7 (4) Delay of diagnosis with genetic criterion removed, n (%) 22 (5) 21 (10) 1 (<1) Combined loss and delay with genetic criterion removed, n (%) 40 (10) 32 (15) 8 (4)
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Figure Legends
411
Figure 1.
412
Flowchart of the study population.
413 414
Figure 2.
415
Survival curve of ARVC patients: pathogenic variant carriers versus non-carriers, showing no significant difference 416
in time from initial diagnosis to first malignant ventricular event.
417
418
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Netherlands ACM registry N = 2052
N = 216 N = 186
N = 121 (56%) N = 111 (60%)
Loss of diagnosis N = 11 (5%)
Loss of diagnosis N = 7 (4%) Diagnosis delay
N = 21 (10%)
Diagnosis delay N = 1 (0.5%)
TFC ≥ 4
Genetics criterion
No MVA No MVA
No MVA 3 MVA (1%)
Probands Relatives
Figure 1
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Supplementary Table 1: Overview of NGS panels employed in probands of our study.
Cardiomyopathy panel (76%)
Arrhythmia panel (5%)
Cardiovascular Disease panel (19%)
ACTC1 ABCC9 ABCC9 DSG2 LMNA PTPN11
ACTN2 AKAP9 ABRA DSP MAP2K1 RAF1
ALPK3 ANK2 ACADVL DTNA MAP2K2 RBM20
BAG3 CACNA1C ACTA1 ELN MYBPC3 RYR1
CrYAB CACNA2D1 ACTA2 EMD MYH11 RYR2
CSRP3 CACNB2 ACTC1 EYA4 MYH6 SCN1B
DES CALM1 ACTN1 FBN1 MYH7 SCN3B
DMD CALM2 ACTN2 FBN2 MYH7B SCN4B
DSC2 CALM3 ACVR2B FBXL22 MYL2 SCN5A
DSG2 CASQ2 AKAP13 FERMT2 MYL3 SDHA
DSP CAV3 AKAP9 FHL1 MYL5 SGCD
FHL1 DES ALMS1 FHL2 MYL7 SHOC2
FLNC DPP6 ANK2 FKRP MYLK SLC25A4
GLA DSC2 ANKRD1 FKTN MYLK2 SLC2A10
HCN4 DSG2 ANKRD2 FLNC MYLK3 SLC8A1
JPH2 DSP ATP2A2 FOXH1 MYO6 SMAD3
JUP GJA5 BAG3 GAA MYOM1 SMYD1
LAMP2 GPD1L BCAR1 GATA4 MYOM2 SMYD2
LMNA HCN4 BMP10 GATAD1 MYOT SNTA1
MIB1 JUP BRAF GDF1 MYOZ1 SOS1
MYBPC3 KCNA5 CACNA1C GJA1 MYOZ2 SYNE1
MYH7 KCNE2 CACNA2D1 GJA5 MYOZ3 SYNE2
MYL2 KCNE3 CACNB2 GJC1 MYPN SYNM
MYL3 KCNH2 CALR3 GLA MYZAP TAZ
NEXN KCNJ2 CAPN1 GLRX3 NEB TBX20
PKP2 KCNJ5 CAPN2 GPD1L NEBL TBX5
PLN KCNJ8 CAPN3 HCN4 NEURL2 TCAP
PRDM16 KCNQ1 CAPNS1 HDAC1 NEXN TGFB2
PRKAG2 LAMP2 CAPZA1 HDAC2 NKX2-5 TGFB3
RBM20 LMNA CAPZA2 HRAS NODAL TGFBR1
RYR2 MYL4 CAPZB ILK NPPA TGFBR2
SCN5A NKX2-5 CASQ2 ITGB1BP2 NOTCH1 TMEM43
TAZ NPPA CAV3 JAG1 NRAP TMOD1
TCAP PKP2 CBL JPH2 NRAS TMPO
TMEM43 PLN CBS JUP NRG1 TNNC1
TNNC1 PRKAG2 CFC1 KBTBD13 OBSCN TNNI3
TNNI3 RYR2 CFL2 KCNE1 OBSL1 TNNT1
TNNT2 SCN1B CHRM2 KCNE2 PAK1 TNNT2
TPM1 SCN2B CMYA5 KCNE3 PALLD TPM1
TTN SCN3B COL3A1 KCNH2 PARVB TPM2
TTR SCN4B COL5A1 KCNJ2 PDE5A TPM3
VCl SCN5A COL5A2 KCNJ5 PDLIM1 TRIM54
SNTA1 COX15 KCNJ8 PDLIM3 TRIM55
TBX5 CRELD1 KCNQ1 PDLIM5 TRIM63
TECRL CRYAB KRAS PDLIM7 TTN
TMEM43 CSRP3 LAMA4 PKP2 TTR
TRDN CTNNA3 LAMP2 PLN TXNRD2
TRPM4 DES LDB3 (ZASP) POLR2M UNC45B
TTN DICER1 LEFTY2 PPP3CA VCL
DMD MIB1 PPP3CB XIRP1
DNAJB6 LIMS1 PPP3R1 XIRP2
DNM1L LIMS2 PRKAG2 ZIC3
DSC2 LMCD1 PRKCE
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Supplementary Table 2: Detailed information on presentation and disease course among probands and relatives who lost definite ARVC diagnosis by exclusion of genetic testing from the TFC.
*TFC score including genetic testing results. Abbreviations: ECG = electrocardiogram; MRI = magnetic resonance imaging; PVC = premature ventricular complex count; SAECG = signal averaged ECG; TAD = Terminal Activation Delay >55ms; TFC = Task Force Criteria; TWI = T wave inversion; VA = sustained ventricular arrhythmia.
ID Family status
Sex Age at presentation
Type of presentation Gene mutation
TFC score*
Non-genetic TFC fulfilled at last follow-up Follow up time (years)
Sustained VA outcome
Heart failure outcome
1 Proband F 41 Hospital admission due to
dyspnea
DSP 4 Repolarization (minor, TWI on ECG), Arrhythmia (minor, PVC count)
2.5 No Yes, at the time of
presentation
2 Proband F 62 Evaluation because of dizziness DSP 4 Arrhythmia (minor, PVC count)
Imaging (minor, MRI)
3.8 No No
3 Proband F 58 Evaluation because of
palpitations
DSP 4 Imaging (major, MRI) 14.4 No No
4 Proband F 54 Evaluation because of dyspnea DSP 4 Repolarization (major, TWI on ECG) 3.6 No No
5 Proband F 62 Evaluation because of
palpitations and chest pain
DSP 4 Depolarization (minor, SAECG) Arrhythmia (minor, PVC count)
5.0 No Yes, 5 years after
presentation
6 Proband F 55 Evaluation because of
presyncope and palpitations
PKP2 5 Repolarization (minor, TWI on ECG), Imaging (major, MRI)
0.1 No No
7 Proband F 25 Evaluation because of
palpitations
PKP2 5 Repolarization (major, TWI on ECG), Arrhythmia (minor, PVC count)
6.7 No No
8 Proband M 67 Evaluation because of
presyncope and palpitations
PKP2 5 Depolarization (minor, TAD) Repolarization (major, TWI)
5.2 No No
9 Proband M 40 Evaluation because of dyspnea PKP2 5 Arrhythmia (minor, Holter)
Imaging (major, echo)
12.2 No Yes, 8 years after
presentation
10 Proband M 38 Evaluation because of
palpitations
DSC2 4 Repolarization (major, TWI on ECG) 1.8 No No
11 Proband F 51 Evaluation because of syncope PKP2 4 Repolarization (minor, TWI on ECG)
Arrhythmia (minor, PVC count)
3.3 No No
12 Relative F 40 Evaluation because of family history
DSP 4 Tissue (minor, biopsy)
Arrhythmia (minor, PVC count)
11.6 No No
13 Relative F 54 Evaluation because of
palpitations and fatigue
DSP 4 Repolarization (minor, TWI on ECG) Arrhythmia (minor, PVC count)
1.2 No No
14 Relative M 46 Evaluation because of family history
PKP2 4 Repolarization (major, TWI on ECG) 1.1 No No
15 Relative M 49 Evaluation because of family history
PKP2 4 Depolarization (minor, TAD) Arrhythmia (minor, PVC count)
11.4 No No
16 Relative F 28 Evaluation because of family history
PKP2 4 Repolarization (minor, TWI on ECG) Arrhythmia (minor, PVC count)
11.4 No No
17 Relative F 14 Evaluation because of family history
DSG2 4 Depolarization (minor, TAD) Arrhythmia (minor, PVC count)
9.9 No No
18 Relative F 26 Evaluation because of family history
PKP2 4 Repolarization (minor, TWI on ECG) Arrhythmia (minor, PVC count)
2.6 No No
