# Non-juvenile familial form of life-threatening arrhythmias caused by the Ryanodine Receptor type 2 c.13823 G>A, p.(Arg4608Gln) pathogenic variant: Atypical catecholaminergic polymorphic ventricular Tachycardia or misdiagnosis?

Sok-Sithikun Bun, Fabien Squara, Didier Scarlatti, Céline Leccia, Florence Kyndt, Emile Ferrari, Cécile Rouzier

## ► To cite this version:

Sok-Sithikun Bun, Fabien Squara, Didier Scarlatti, Céline Leccia, Florence Kyndt, et al. Non-juvenile familial form of life-threatening arrhythmias caused by the Ryanodine Receptor type 2 c.13823 G>A, p.(Arg4608Gln) pathogenic variant: Atypical catecholaminergic polymorphic ventricular Tachycardia or misdiagnosis?. Forensic Science International: Genetics, 2025, 76, pp.103238. 10.1016/j.fsigen.2025.103238. hal-05241204

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Submitted on 5 Sep 2025

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Case Report

Non-juvenile familial form of life-threatening arrhythmias caused by the Ryanodine Receptor type 2 c.13823 G>A, p.(Arg4608Gln) pathogenic variant: Atypical catecholaminergic polymorphic ventricular Tachycardia or misdiagnosis?

Sok-Sithikun Bun<sup>a, *, ◎</sup>, Fabien Squara<sup>a</sup>, Didier Scarlatti<sup>a</sup>, Céline Leccia<sup>d</sup>, Florence Kyndt<sup>e</sup>, Emile Ferrari<sup>a</sup>, Cécile Rouzier<sup>b, c</sup>

<figure><img src="image_3.png" /></figure>

ARTICLE INFO

Keywords:

Calcium release deficiency syndrome
Catecholaminergic polymorphic ventricular
tachycardia
Ryanodine Receptor Type 2
R4608 Mutation
Cardiac arrest

A B S T R A C T

**Background:** Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare inherited channelopathy, responsible for potentially lethal malignant arrhythmic episodes. Atypical non-juvenile form of CPVT may not mislead an alternative diagnosis of calcium release deficiency syndrome (CRDS).

**Case:** The index case was a 58 years-old woman who experienced aborted sudden cardiac arrest. The initial complete diagnostic workup (including norepinephrine challenge) was completely negative. She was implanted with an entirely subcutaneous defibrillator. During her follow-up, she received an appropriate electrical shock (ventricular fibrillation) despite β-blocker treatment. Three sisters (46, 40 and 18 years-old) as well as 2 cousins, one paternal uncle and one paternal aunt had sudden cardiac deaths (SCD) without etiology in the family history. There were no additional reports of pregnancy loss, neonatal death, seizures or SCD among the family members. The genetic analysis in this proband revealed a missense pathogenic variant c.13823 G>A, p.(Arg4608Gln) in the *RYR2* gene, encoding the Ryanodine Receptor type 2. This c.13823 G>A, p.(Arg4608Gln), variant in the *RYR2* gene was supposed to be a potential disease-causing variant in CPVT. Unfortunately, before the end of the proband's genetic analysis, her 20 years-old daughter experienced SCD, whilst being implanted with an insertable cardiac monitor. Familial segregation analysis confirmed the four symptomatic sisters harbor also the same variant confirming the pathogenic role of this variant. We also identified 7 carriers who were clinically negative for CPVT in the next generation. Whole were treated with Nadolol 80 mg per day, and the follow-up was uneventful after twenty-four months.

**Conclusion:** The Ryanodine Receptor type 2 c.13823 G>A, p.(Arg4608Gln) pathogenic variant is described in a malignant familial form of CRDS.

1. Introduction

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare inherited cardiac ion channelopathy, responsible for potentially lethal malignant arrhythmic episodes. CPVT is usually observed in

juvenile patients without cardiac structural disease. Sudden cardiac deaths (SCD) may be observed in 30 % of the cases, and usually consecutive to adrenergically-mediated arrhythmias (triggered by exercise or emotion) [1]. If not treated, CPVT is a highly lethal condition with 80 % of affected patients experiencing recurrent syncope. The main

Abbreviations: CPVT, Catecholaminergic Polymorphic Ventricular Tachycardia; CRDS, Calcium Release Deficiency Syndrome; ECG, Electrocardiogram; EST, Exercise stress testing; SADS, Sudden Arrhythmic Death Syndrome; SCD, Sudden cardiac death; VF, Ventricular fibrillation.

* Correspondence to: Pasteur University Hospital, 30 Voie Romaine, Nice, France.

E-mail address: soksithikun@hotmail.com (S.-S. Bun).

<footnote><sup>a</sup> Cardiology Department, Pasteur University Hospital, Nice, France</footnote>

<footnote><sup>b</sup> Medical Genetic Department, Archet University Hospital, Université Côte d'Azur, Nice, France</footnote>

<footnote><sup>c</sup> Inserm U1081, CNRS UMR7284, IRCAN, Université Côte d'Azur, Nice, France</footnote>

<footnote><sup>d</sup> Forensic Medicine Department, Archet University Hospital, Nice, France</footnote>

<footnote><sup>e</sup> Institut du Thorax, Centre Hospitalier Universitaire de Nantes, France</footnote>
responsible gene, *RYR2*, encodes the cardiac isoform of the ryanodine
receptor (RyR2), and accounts for 55 % of the pathogenic variants. RyR2
mediates the calcium release from the sarcoplasmic reticulum, required
for sarcomere contraction. The different pathogenic variants in the
*RYR2* gene increase calcium release (or deficiency) and may trigger
malignant ventricular arrhythmias. The vast majority of CPVT cases are
related to gain-of-function variants in the RyR2 protein. In 2021, a
distinct inherited arrhythmia syndrome caused by loss-of-function var-
iants in *RYR2* has been discovered, termed *calcium release deficiency
syndrome* (CRDS) [2–4]. Patients with CRDS are at risk for ventricular
fibrillation (VF) but do not appear to have provocable ventricular
tachyarrhythmias during exercise stress testing (EST). We report here a
missense variant in the *RYR2* gene, in a family presenting a non-juvenile
form of malignant CPVT. Given the atypical presentation of CPVT in this
family, the alternate diagnosis of CRDS will be discussed.

## 2. Methods

The analysis study was approved by the Ethics Committee of our
Hospital and conforms to the principles outlined in the Declaration of
Helsinki. Alive individuals signed a written informed consent to
participate, in accordance with international review board guidelines of
our institution. Detailed family history was obtained including age of
presentation, initial symptoms, and 12-lead electrocardiogram (ECG).
Genomic DNA from the proband and the family members was extracted
from peripheral blood lymphocytes by standard protocols. [5] A panel of
109 genes involved in SCD-associated pathologies was sequenced using
the IDT Cardio CECAS_A_v1 (Sophia Genetics) capture kit and an Illu-
mina sequencer. Bioinformatic analysis used the Sophia Genetics pipe-
line on the Sophia-DDM platform. The depth was 30x minimum. The
identified variant was confirmed by Sanger sequencing.

## 3. Results

### 3.1. *Phenotype*

The index case was a 58 years-old woman who experienced aborted

SCD. The initial complete diagnostic workup (including coronary angi-
ography, EST, and norepinephrine challenge) was completely negative.
She was implanted with an entirely subcutaneous defibrillator, with an
initial diagnosis of idiopathic VF. During her follow-up, she received an
appropriate electrical shock (caused by VF), despite being treated with a
β-blocker agent. Three sisters experienced Sudden Arrhythmic Death
Syndrome (SADS) without etiology in the family history (age of 46, 40
and 18). The fatal events occurred in Algeria, without definite etiology.
There were no additional reports of pregnancy loss, neonatal death,
seizures or SCD among the family members.

### 3.2. *Genotype*

The genetic analysis in proband II6 revealed the heterozygous
c.13823 G>A, p.(Arg4608Gln), missense variant in the *RYR2* gene
(NM_001035.2, GRCh37: Chr1:237957207 G>A). Unfortunately, before
the result of the proband's genetic analysis, her 20-years old daughter
presented SADS, during light activity, whilst being implanted with an
implantable loop recorder (Fig. 1). Molecular autopsy confirmed she
was carrier of the *RYR2* variant.

Sanger sequencing was performed in twenty-two family members
and confirmed that probands II1 and II3 are obligate carriers. Proband
II8 is also heterozygous for the *RYR2* variant, while the asymptomatic
sister II10 does not carry the *RYR2* variant.

### 3.3. *Genotype-Phenotype*

Clinical examinations including baseline ECG, EST of asymptomatic
carriers for CPVT were negative. All were treated with Nadolol 80 mg
per day, and the follow-up was uneventful after forty-eight months.
None of the negative carriers were diagnosed with CPVT.

## 4. Discussion

Cardiac arrest is devastating, particularly in young and previously
healthy individuals. The identification of the pathogenic variant
responsible for the disease helped detecting the genetic carriers in the

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Family pedigree. At the bottom, is illustrated an implantable loop recorder recording of a fatal episode (polymorphic ventricular tachycardia) occurring in the daughter of the index case. One may notice the presence of sinus tachycardia (mean cycle length 410 ms) immediately preceding the occurrence of the malignant ventricular arrhythmia event. Black round/square means clinically diagnosed patients. White round/square means negative on clinically assessment. Plus signs indicate genetic carriers of *RYR2* c.13823 G>A, p.(Arg4608Gln). Minus signs indicate non-genetic carriers. Slashed line indicates deceased individuals.</figcaption></figure>
family, including the asymptomatic ones, who are at risk for SCD.

CPVT is a rare cardiac channelopathy significantly lethal when non treated. This disease is usually associated with a normal structural heart - though a co-phenotype with left ventricular non-compaction cardiomyopathy has recently been reported – with an estimated mortality between 30 % and 50 % [6].

A *RYR2* c.13823 G>A, p.(Arg4608Gln), pathogenic variant is described here in a family (13 genetic carriers) with a rare non-juvenile but highly malignant form. Noteworthy, at the moment, fatal events only occurred in female members in our CPVT family, with late-onset CPVT (five SADS, included one aborted in the proband, the youngest was 20 years-old). One has to remember that Sy et al. described a bimodal distribution for CPVT symptom onset with different clinical presentation between late-onset CPVT (32–48 years old) and those with early-onset CPVT (10–20 years old). [7] In their series, the authors also suggested that patients with late-onset CPVT were more often female, with an associated lower risk of SCD. Priori et al. also observed that *RYR2* (-) CPVT patients were significantly older at first presentation and were also more likely to be female in comparison with *RYR2* (+) CPVT patients. [8] This is in contrast with our observation. Of note, Sumitomo defined a CPVT classification based upon age of onset: juvenile type before the age of 20, and adult type after the age of 20. [9] Recently, Bosch et al. reported the novel *RYR2* p.I11S pathogenic variant, found in 5 members from a family of 14, all carriers were clinically diagnosed for CPVT. [10] Noteworthy, none of the newly identified carriers in our family showed clinical presentation suggestive for CPVT. One explanation may be the fact that highly variable expressivity and incomplete penetrance may be seen in almost 85 % of CPVT families. [11] The other hypothesis would be an alternate likely diagnosis of CRDS.

The c.13823 G>A, p.(Arg4608Gln) variant was classified pathogenic using the ACMG classification (PM1, PM2, PM5, PP3, PS3). [12] This substitution was not found in the Genome Aggregation Database (GnomAD v3) (http://gnomad.broadinstitute.org/), changes a highly-conserved arginine (Cys) into a glutamine (Gln) at amino acid position 4608 and is predicted pathogenic by in silico tools including CADD v1.4 score (PHRED 32) and the REVEL score (0.8849). A pathogenic substitution was previously described at this position changing the arginine into a tryptophane instead. [13] The p.(Arg4608Gln) variant is reported pathogenic in ClinVar (RCV001248799.15) and was previously identified in two family members (40 year-old male and 14 year-old female patients) diagnosed for CPVT. [14] Other descriptions of *RYR2* c.13823 G>A, p.(Arg4608Gln) variant (summarized in Tables 1 and 2) concerned SADS cohorts: a 41 year-old male isolated proband; [15,16] and more recently in an infant with idiopathic VF [17]. Interestingly Roston et al. showed that the p.(Arg4608Gln) markedly inhibited caffeine response compare to controls, in favor of a loss of function effect

<caption>**Table 1**</caption>

Summary of the family members harboring the *RYR2* c.13823 G>A, p. (Arg4608Gln) variant.

<table><caption>**Table 2**</caption><thead><tr><th>Patient</th><th>Symptoms</th><th>Implantable cardioverter defibrillator</th><th>Age of SADS</th><th>Genotype</th></tr></thead><tbody><tr><td>II1</td><td>SADS</td><td>No</td><td>46</td><td>NA</td></tr><tr><td>II3</td><td>SADS</td><td>No</td><td>40</td><td>NA</td></tr><tr><td>II5</td><td>SADS</td><td>No</td><td>18</td><td>NA</td></tr><tr><td>II6</td><td>Aborted sudden cardiac arrest</td><td>Yes</td><td>58</td><td>c.13823 G>A</td></tr><tr><td>II8</td><td>Syncope</td><td>Yes</td><td>52</td><td>c.13823 G>A</td></tr><tr><td>III1</td><td>Asymptomatic</td><td>No</td><td></td><td>c.13823 G>A</td></tr><tr><td>III5</td><td>Asymptomatic</td><td>No</td><td></td><td>c.13823 G>A</td></tr><tr><td>III6</td><td>Asymptomatic</td><td>No</td><td></td><td>c.13823 G>A</td></tr><tr><td>III8</td><td>Asymptomatic</td><td>No</td><td></td><td>c.13823 G>A</td></tr><tr><td>III9</td><td>Asymptomatic</td><td>No</td><td></td><td>c.13823 G>A</td></tr><tr><td>III10</td><td>Asymptomatic</td><td>No</td><td></td><td>c.13823 G>A</td></tr><tr><td>III13</td><td>SADS</td><td>No</td><td>20</td><td>c.13823 G>A</td></tr><tr><td>III14</td><td>Asymptomatic</td><td>No</td><td></td><td>c.13823 G>A</td></tr></tbody></table>

Summary of patients harboring the *RYR2* c.13823 G>A, p.(Arg4608Gln) variant, reported in the literature.

<table><thead><tr><th>Author</th><th>Sex</th><th>Age (y)</th><th>Circumstances of event</th><th>Family Diagnosis</th></tr></thead><tbody><tr><td><strong>Wong LC</strong><br><strong>2014</strong></td><td>Male</td><td>40</td><td>Inactive (awake)</td><td>CPVT</td></tr><tr><td><strong>Lahrouchi N</strong><br><strong>2017</strong></td><td>Female</td><td>14</td><td>Inactive (sleep)</td><td>CPVT</td></tr><tr><td><strong>Frontera A</strong><br><strong>2019</strong></td><td>Male</td><td>41</td><td>Light activity (chest pain before death)</td><td>SADS cohort (post-mortem)</td></tr><tr><td><strong>Raju H</strong><br><strong>2019</strong></td><td>NA</td><td>mean age<br>12.7 ± 3.7</td><td>NA</td><td>IVF</td></tr><tr><td><strong>Our series</strong><br><strong>2025</strong></td><td>NA</td><td>mean age<br>32.9 ± 14.4</td><td>NA</td><td>SADS</td></tr><tr><td></td><td>Female</td><td>58</td><td>Light activity (awake)</td><td>SADS</td></tr><tr><td></td><td>Female</td><td>52</td><td></td><td>Syncope</td></tr><tr><td></td><td>Male</td><td>28</td><td></td><td>Asymptomatic</td></tr><tr><td></td><td>Male</td><td>35</td><td></td><td>Asymptomatic</td></tr><tr><td></td><td>Female</td><td>20</td><td>Light activity (awake)</td><td>SADS</td></tr><tr><td></td><td>Male</td><td>30</td><td></td><td>Asymptomatic</td></tr><tr><td></td><td>Male</td><td>16</td><td></td><td>Asymptomatic</td></tr><tr><td></td><td>Female</td><td>26</td><td></td><td>Asymptomatic</td></tr><tr><td></td><td>Male</td><td>32</td><td></td><td>Asymptomatic</td></tr></tbody></table>

CPVT: Catecholaminergic Polymorphic Ventricular Tachycardia; IVF: Idiopathic Ventricular Fibrillation; NA: Non-available; SADS: Sudden Arrhythmic Death Syndrome.

of this variant [13].

The atypical presentation of this non-juvenile form of CPVT in our family members with negative EST may rise the suspicion of CRDS [2, 13]. EST and adrenaline tests conducted in this family yielded normal results. Furthermore, the fatal event in the proband's daughter and the arrhythmic episodes in the proband did not occur during exercise. As opposed to CPVT which is characterized by the occurrence of bidirectional ventricular tachycardia in response to catecholamine stress; CRDS clinical phenotype is undetectable, and clinicians cannot confirm CRDS diagnosis without access to *RYR2* in vitro analyses. There was an urgent need to develop a reliable clinical test for diagnosing CRDS. Ni et al. just published the possibility to analyze a specific repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause, which is a hallmark of CRDS. [18] Ventricular pacing maneuvers were not performed in our proband because she was implanted with an entirely subcutaneous defibrillator. But we may discuss the possibility to propose an electrophysiological study instead, using a long-burst, long-pause, and short-coupled ventricular extra-stimulus sequence. The familial clinical final diagnosis could then be revised to CRDS.

The differential diagnosis between CPVT and CRDS is of critical importance, to enable appropriate strategy and optimal care of survivors and their family members. [19]

Actually, a preventive strategy (extreme physical activity avoidance), with pharmacologic therapy (Nadolol), has been proposed to all the seven asymptomatic carriers identified in this family, and the close follow-up is uneventful until now. This attitude is in line with the current recommendations supporting early genetic testing for clinical management and therapeutic decisions involving family members even in young children because SCD in infants may be the first manifestation of CPVT. [20] In the likely alternate diagnosis of CRDS, then another preventive pharmacologic therapy could be discussed in the family members switching to flecainide instead. [21] Further monitoring in this family will be needed to answer this question.

## 5. Conclusion

A *RYR2* c.13823 G>A, p.(Arg4608Gln) pathogenic variant was reported with a non-juvenile familial malignant form of CPVT. SADS occurred in 5 female members from this family. Early diagnosis and
genetic identification of seven family carriers helped adopting preven-
tive measures and therapy, likely avoiding arrhythmic events.

CRediT authorship contribution statement

**Bun Sok-Sithikun:** Writing – original draft, Validation, Methodology, Investigation, Data curation, Conceptualization. **Kyndt Florence:** Data curation. **Leccia Céline:** Data curation. **Rouzier Cécile:** Writing – review & editing, Visualization, Validation, Data curation. **Ferrari Emile:** Supervision. **Scarlatti Didier:** Data curation. **Squara Fabien:** Data curation.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We thank Sara Halawi, genetic counselor.

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