Detection of gene mutation in the prognosis of a patient with arrhythmogenic right ventricular cardiomyopathy: a case report

Abstract

Background
Arrhythmogenic right ventricular cardiomyopathy (ARVC), or more recently known as arrhythmogenic cardiomyopathy (ACM), is an heritable disorder of the myocardium characterized by progressive fibrofatty replacement the heart muscle and risk of ventricular arrhythmias and sudden cardiac death (SCD). We report a case study to demonstrate the role of gene mutation detection in risk stratification for primary prevention of SCD in a young patient diagnosed with ARVC.

Case presentation
A 15-year-old Asian (Vietnamese) male patient with no history of documented tachyarrhythmia or syncope and a family history of potential SCD was admitted due to palpitations. Clinical findings and work-up including cardiac magnetic resonance imaging (MRI) were highly suggestive of ARVC. Gene sequencing was performed for SCD risk stratification, during which PKP2 gene mutation was found. Based on the individualized risk stratification, an ICD was implanted for primary prevention of SCD. At 6 months post ICD implantation, the device detected and successfully delivered an appropriate shock to terminate an episode of potentially fatal ventricular arrhythmia. ICD implantation was therefore proven to be appropriate in this patient.

Conclusions
While gene mutations are known to be an important factor in the diagnosis of ARVC according to the 2010 Task Force Criteria and recent clinical guidelines, their role in risk stratification of SCD remains controversial. Our case demonstrated that when used with other clinical factors and family history, this information could be helpful in identifying appropriate indication for ICD implantation.

Full text

Phanetal. Journal of Medical Case Reports (2024) 18:49
https://doi.org/10.1186/s13256-023-04326-w
CASE REPORT Open Access
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Journal of
Medical Case Reports
Detection ofgene mutation intheprognosis
ofapatient witharrhythmogenic right
ventricular cardiomyopathy: acase report
Dinh Phong Phan1,2*, Tuan Viet Tran1,2, Vo Kien Le1 and Tuan Viet Nguyen2
Abstract
Background Arrhythmogenic right ventricular cardiomyopathy (ARVC), or more recently known as arrhythmogenic
cardiomyopathy (ACM), is an heritable disorder of the myocardium characterized by progressive fibrofatty replace-
ment the heart muscle and risk of ventricular arrhythmias and sudden cardiac death (SCD). We report a case study
to demonstrate the role of gene mutation detection in risk stratification for primary prevention of SCD in a young
patient diagnosed with ARVC.
Case presentation A 15-year-old Asian (Vietnamese) male patient with no history of documented tachyarrhythmia
or syncope and a family history of potential SCD was admitted due to palpitations. Clinical findings and work-up
including cardiac magnetic resonance imaging (MRI) were highly suggestive of ARVC. Gene sequencing was per-
formed for SCD risk stratification, during which PKP2 gene mutation was found. Based on the individualized risk strati-
fication, an ICD was implanted for primary prevention of SCD. At 6 months post ICD implantation, the device detected
and successfully delivered an appropriate shock to terminate an episode of potentially fatal ventricular arrhythmia.
ICD implantation was therefore proven to be appropriate in this patient.
Conclusions While gene mutations are known to be an important factor in the diagnosis of ARVC according
to the 2010 Task Force Criteria and recent clinical guidelines, their role in risk stratification of SCD remains controver-
sial. Our case demonstrated that when used with other clinical factors and family history, this information could be
helpful in identifying appropriate indication for ICD implantation.
Keywords Arrhythmogenic right ventricular cardiomyopathy (ARVC), Gene muations, PKP2 gene, Case report
Background
Arrhythmogenic right ventricular cardiomyopathy
(ARVC), or more recently known as arrhythmogenic
cardiomyopathy (ACM), is an heritable disorder of the
myocardium characterized by progressive myocardial
changes and risk of ventricular arrhythmias and sudden
cardiac death (SCD). First described in the late 1970s
and early 1980s [1], histopathological characterization
of the right ventricle (RV) identifies multiple changes,
most notably the presence of progressive fibrofatty or fat
replacement of the myocardium, leading to RV dilatation
and dysfunction [2]. is process forms heterogeneous
zones of the myocardium correlated with arrhythmo-
genic substrates, which trigger the occurrence of ventric-
ular tachycardias (VT) and ventricular fibrillation (VF)
that can lead to SCD [3, 4]. However, recent studies have
shown that biventricular involvement is more prevalent
than previously thought and therefore, the term AVRC
*Correspondence:
Dinh Phong Phan
phong.vtm@gmail.com
1 Cardiac Electrocardiogram and Electrophysiology Laboratory, Vietnam
National Heart Institute, Bach Mai Hospital, 78 Giai Phong St., Hai Ba
Trung, Hanoi, Vietnam
2 Hanoi Medical University, 1 Ton That Tung St., Dong Da, Hanoi, Vietnam
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Phanetal. Journal of Medical Case Reports (2024) 18:49
is being replaced by arrhythmogenic cardiomyopathy
(ACM) [5] It has been reported that 73% of ARVC index
patients carry mutations in genes encoding the desmo-
somal proteins [6, 7] necessary for the maintenance of
stable intercellular connections. e prevalence of these
gene mutations ranges from 28 to 58% [8, 9]. TGFB3,
RYR2, TTN, TNEM43, DES, DSP, PKP2, DSG2, DSC2,
JUP, PLN, LMNA, SCN5A, and CTNNA3 have all been
identified as playing a role in the pathogenesis of ARVC
in recent studies [10]. is finding provides the founda-
tion for the latest recommendation in European Society
of Cardiology (ESC) guidelines as well as Heart Rhythm
Society (HRS) consensus to consider gene mutations as
a criterion for ARVC diagnosis and risk stratification [11,
12]. Nevertheless, the role of gene mutations in guiding
treatment decisions remains controversial, particularly in
the risk stratification of primary prevention of SCD [13].
We report a case study to demonstrate the role of gene
mutation detection in risk stratification for treatment
decisions.
Case presentation
A 15-year-old Asian (Vietnamese) male high school
student as well as basketball player presented with the
first-ever episode of palpitations. He had never had syn-
cope or presyncope, documented arrhythmia or been
diagnosed with cardiovascular diseases. His 27-year-old
brother had died suddenly one year ago due to out of hos-
pital cardiac arrest. Most likely cause of death was iden-
tified as arrhythmia by emergency physicians after other
differentials such as cerebral vascular stroke, myocardial
infarction, congenital and acquired cardiac disease were
excluded by imaging, blood tests. On examination, his
vital signs were normal with no clinical signs of heart fail-
ure. His electrocardiography (ECG) on admission (Fig.1)
showed frequent and various forms of premature ven-
tricular complexes (PVC) with negative T waves in leads
V1–V3.
Transthoracic echocardiography showed mildly dilated
right ventricle with no other significant structural or
functional abnormalities. e 24-h ECG ambulatory
(Fig.2) revealed significant PVC burden, accounting for
10.5% of the total number of heart beats. At least three
distinct PVC morphologies were observed. ere were
occasionally coupled PVCs but no non-sustained or sus-
tained VT was captured.
Electrophysiology (EP) study was indicated for two
purposes: (1) to ablate the frequent PVCs, and (2) to con-
duct programmed electrical stimulation (PES) to induce
sustained ventricular arrhythmias for risk stratification.
During the procedure, frequent PVCs with various pat-
terns were observed. ese PVCs originated from the RV
at different sites of the postero-lateral wall, proximal to
the tricuspid annulus. Multiple attempts of mapping and
radiofrequency ablation failed to terminate all PVCs. PES
delivered at the RV apex with two extra stimuli induced
non-sustained episodes of VT repeatedly (Fig.3).
Cardiac Magnetic Resonance Imaging (MRI) showed
enlarged RV with dyskinesia and reduced ejection frac-
tion (RV ejection fraction 34.97%). An aneurysm close to
the RV apex was also observed. Late-enhancement signal
with Gadolinium showed diffused fatty infiltration in the
RV free wall (Fig.4). Left ventricular structure and func-
tion was normal (LV ejection fraction 62%).
We then performed molecular-genetic analysis using
next-generation sequencing (NGS) methods to identify
Fig. 1 Electrocardiography on admission showing baseline rhythm was sinus rhythm, T wave inversion in leads V1–V3, with frequent
and polymorphic premature ventricular complexes
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Phanetal. Journal of Medical Case Reports (2024) 18:49
Fig. 2 24-h ambulatory Electrocardiography: two consecutive premature ventricular complexes variants were recorded
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Phanetal. Journal of Medical Case Reports (2024) 18:49
gene mutations for further risk stratification. A muta-
tion in the PKP2 gene which encodes Plakophilin-2
protein was identified (Fig. 5). The most prevalent
cause of ARVC is a heterozygous mutation in this
Fig. 3 Programmed electrical stimulation induced a non-sustained ventricular tachycardia
Fig. 4 Cardiac Magnetic Resonance Imaging showed intramyocardial late gadolinium enhancement due to diffused fibrofatty scar involving the RV
free wall
Gene Genomic
location
Variant
type
Nucleotide
changes
Location Molecular
consequence
ACMG Evidence
PKP2 chr12:
32841207
SNV (NM_001005
242.3):
c.1379-2A>G
intron 5 of 12
position 9559 of
9560
Splice
acceptor
Pathogenic
(ARVC/D)
PVS1,PP5,
PM2-
supporting
Fig. 5 The results of molecular-genetic analysis
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Phanetal. Journal of Medical Case Reports (2024) 18:49
gene. So far, more than 200 mutations in the PKP2 gene have been documented, the majority of which are point
mutations.
Finally, patient was diagnosed with ARVC according to the Modified Task Force criteria for ARVC proposed by the
International Task Force of ESC and International Society and Federation of Cardiology in 2010. e specific diagnos-
tic criteria were:
1. Major criterion: cardiac MRI found RV dyskinesia
and RVEF 34.97%.
2. Major criterion: T wave inversion in leads V1–V3 on
ECG
3. Minor criterion: 9899 PVCs on Holter ECG.
4. Major criterion: the PKP2 gene mutation.
After a thorough consideration of all risk factors as
well as careful discussion with the patient’s parents, we
decided to implant an implantable cardioverter defibrilla-
tor (ICD) for primary prevention of SCD. Patient was ini-
tially discharged on beta-blocker (bisoprolol 5mg daily).
After one month, amiodarone 100mg daily was started
when ICD check found many episodes of non-sustained
VT.
Follow‑up andoutcome
At 6months follow-up, the patient experienced a spon-
taneous episode of fast VT or VF, a potentially fatal ven-
tricular arrhythmia, which was successfully terminated
by an ICD shock (Fig.6).
Dicussion
ARVC is a heritable cardiomyopathy which may cause
life-threatening ventricular arrhythmias leading to SCD.
Fibrofatty replacement of RV myocardium remains to be
the main histopathological characteristic of the disease
[1, 2]. In 2010, the Task Force Criteria (TFC) for clini-
cal diagnosis of the ARVC based on multiple factors was
proposed by experts in the field of heart failure and car-
diomyopathy. In 2019, HRS published an Expert Con-
sensus Statement on Evaluation, Risk Stratification, and
Management of Arrhythmogenic Cardiomyopathy, in
which ACM is defined as the disease in heart muscle that
involves the RV, left ventricle, or both [12]. e patho-
physiological feature is fibrofatty infiltration of myocar-
dium which may predispose patients to life-threatening
arrhythmias and ventricular dysfunction. ACM are clas-
sified into 3 phenotypic variants including the classic
ARVC, ALVC (arrhythmogenic left ventricular cardio-
myopathy) and the disease involving both the ventricles.
e diagnostic criteria for ARVC variant were based on
major and minor criteria of the 2010 TFC [19]. Based on
these diagnostic criteria, our patient met the diagnosis of
definite ARVC.
In the 2010 TFC, gene mutation is considered as one
of the major diagnostic criteria in the family history sec-
tion. Specifically, identification of a pathogenic or likely
pathogenic ACM mutation in the patient under evalua-
tion is categorized as one of the major diagnostic criteria.
Genetic analysis of our patient reveals the presence of a
mutation of the PKP2 gene, which has been shown to be
one of the mutations potentially related to ARVC.
e gene mutation in this patient changes a single
nucleotide at the position NM_001005242.3: c.1379-
2A > G belongs to the PKP2 gene’s intron region. We used
Clinvar and Varsome tool to characterize the mutation
and applied the American College of Medical Genetics
and Genomics (ACMG) criteria to determine its patho-
genicity [14]. Based on these databases, this mutation
belongs to a category of mutations that have the potential
to cause ARVC. PKP2mutations are also the most com-
mon cause of ARVC in some populations. ePKP2gene
encodes the synethis of a protein called plakophilin 2,
which makes up structures called desmosomes. ese
structures form junctions that attach cells to one another.
Abnormalities in the binding protein trigger myocardial
remodeling and fat replacement process which may lead
to arrthymia. PKP2 mutations play an important role in
the pathogenesis and progression of ARVC [15, 16].
According to the findings of Judith et al. the mutation
detection prevalence in ARVC patients was 63%, with
PKP2 mutations accounted for 46% of all mutations [17].
In addition, a study on 90 ARVC patients in China by
Jingru Bao et al. [18] revealed 57 subjects (63%) having
genetic mutations, 58% of which occurred in the PKP2
gene. Furthermore, the study’s findings demonstrated
that ARVC patients with a gene mutation had a higher
risk of VT than those without mutation. Similar finding
was also observed in patients with and without PKP2
gene mutation. is suggests that gene mutations, even if
occurring in a single-gene, especially the PKP2 gene, can
be a predictor of the risk of cardiovascular events associ-
ated with ventricular arrhythmias and sudden death.
SCD due to ventricular arrhythmias can be prevented
by ICD implantation [11]. Expert consensus has recom-
mended that in ARVC patients, ICD is indicated for
secondary prevention in patients with aborted cardiac
arrest or hemodynamically unstable sustained VT, and
for primary prevention in patients who have high risk
of ventricular arrhythmias and SCD [12]. As our patient
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Phanetal. Journal of Medical Case Reports (2024) 18:49
Fig. 6 ICD detected (A) and delivered an appropriate shock (C) to terminate a fast VT or VF after a failed ATP (antitachycardia pacing) attempt (B)
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Phanetal. Journal of Medical Case Reports (2024) 18:49
had no history of aborted SCD, ventricular arrhythmias
associated syncope, sustained VT, or severely reduced
LV ejection fraction on admission, risk factors for
ventricular arrhythmias should be assessed to decide
whether ICD implantation was necessary. According to
the risk stratification guidelines recommended by the
2019 HRS Expert Consensus Statement on Evaluation,
Risk Stratification, and Management of Arrhythmo-
genic Cardiomyopathy, our patient met only four
minor risk factors for ventricular arrhythmias (male
sex, > 1000 PVCs/24h, RV dysfunction [34.97% on car-
diac MRI] and proband status). Accordingly, the indica-
tion for primary prevention with an ICD for this patient
was a class IIb recommendation with the level of evi-
dence B. However, considering his family history with
potential SCD in his older brother, the result of gene
mutation and presuming that the disease’s severity may
progress in the future, and with the family’s preference,
a decision was made to implant an ICD for primary
prevention of SCD. At 6months post implantation, the
patient experienced palpitations and near-syncope. A
sustained fast VT or VF, a potentially fatal ventricular
arrhythmia with an average cycle length of 229ms, was
detected and successfully terminated by an ICD shock.
e decision of ICD implantation was finally proven to
be appropriate for this patient.
Conclusions
Gene mutations are known to be an important factor in
the diagnosis of ARVC according to TFC 2010 criteria
and later clinical guidelines. Although the role of gene
mutation in risk stratification remains controversial, it
still plays an important role in individualized risk strat-
ification and management. In this case, gene mutation,
along with other clinical factors and family history, was
proven to be helpful in guiding treatment decisions of
ICD implantation for primary prevention of SCD in a
young patient diagnosed with ARVC.
Acknowledgements
We wish to thank the Vietnam National Heart Institute for providing us the
opportunity to publish this case report.
Author contributions
Phong Phan Dinh was a major contributor in writing the manuscript. Tuan Viet
Tran and Tuan Viet Nguyen coordinated the writing and managed the submis-
sion of the manuscript. Phong Phan Dinh, Vo Kien Le, Tuan Viet Tran were the
main physicians in charge of providing care and implantation the ICD to the
patient. All authors read and approved the final manuscript.
Funding
The authors declare that they had no financial support for this case report.
Availability of data and materials
The data supporting this study is with the author and has been included
within the manuscript.
Declarations
Ethics approval and consent to participate
Ethical approval is not required at our institution to publish an anonymous
case report.
Consent for publication
Written informed consent was obtained from the patient’s parents for publica-
tion of this case report and any accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of this journal.
Competing interests
No conflicts of interest.
Received: 20 February 2023 Accepted: 18 December 2023
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