Unexplained cardiac arrest (idiopathic ventricular fibrillation): clinical and genetic characteristics

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INTRODUCTION

Sudden cardiac death (SCD) is the most common cause of mortality from cardiovascular diseases. Annually, 1–3 individuals per 100,000 people aged <35 years suddenly die [1, 2]. Studies have reveald that the frequent underlying cause of sudden cardiac arrest is inherited cardiac channelopathies [3, 4]. Autopsy findings of cardiomyopathy can be confirmed by postmortem genetic testing [5]. However, 30–40% of SCD cases in young adults remain unexplained [4, 6, 7]. Patients who survive cardiac arrest after administered cardiopulmonary resuscitation (CPR) may have genetic diseases for which genetic testing is mandatory. Such patients should undergo a comprehensive clinical evaluation focused on identifying the causative disease. If no aetiology is found, the patient is diagnosed with unexplained cardiac arrest (UCA) or idiopathic ventricular fibrillation (IVF). IVF is defined as UCA in a resuscitated patient showing no abnormalities on electrocardiogram (ECG) and in whom known cardiac, respiratory, metabolic, and toxicologic causes have been excluded by clinical evaluation [3, 4]. Studies have shown that IVF accounts for 5–7% of all out-of-hospital cardiac arrests [8].

According to the current European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society expert consensus statement on the state of genetic testing for cardiac diseases (EHRA/HRS/APHRS/LAHRS-2022) [9], genetic testing for diagnostically significant variants is recommended in UCA survivors in addition to a comprehensive clinical evaluation, and if detected, cascade screening of relatives is warranted [10].

In previous studies concerning the diagnostic use of postmortem genetic testing, a series of unexplained cardiac deaths in 26% of cases revealed the presence of allegedly pathogenic variants in genes associated with major channelopathies, including catecholaminergic polymorphic ventricular tachycardia (CPVT) (RYR2 gene), long QT syndrome (LQTS) types 1–3 (KCNQ1, KCNH2, and SCN5A genes), and Brugada syndrome type 1 (SCN5A gene) [7]. Genetic screening of autopsy material from 302 individuals who died of sudden arrhythmic death syndrome was recently conducted. According to the 2015 American College of Medical Genetics and Genomics (ACMG) criteria, pathogenic and likely pathogenic variants in genes associated with channelopathies were identified in 11% of cases [11]. Additionally, pathogenic variants were identified in 2% of cases in genes associated with cardiomyopathies, indicating a structural cause of UCA that may have not been detected. The diagnostic yield increased by an average of 30% with the implementation of molecular genetic screening and clinical examination of family members [10, 11]. Genetic testing of UCA survivors using extended panels revealed the number of channelopathies and cardiomyopathies with an alleged pathogenic variant ranging from 3% to 27% [8, 12, 13].

The present study analyzed a cohort of patients with UCA caused by IVF who were successfully resuscitated and underwent implantation of cardioverter-defibrillator (ICD). Genetic alterations were assessed in these patients.

This study aimed to evaluate the clinical and genetic characterization of inherited arrhythmias in patients who survived UCA.

MATERIALS AND METHODS

Twenty patients (10 men, 10 women) aged 15–55 years with documented ventricular tachycardia (VT)/ventricular fibrillation (VF) on ECG were enrolled consecutively. The median follow-up period was 3 years.

Patients who had UCA with documented VT or VF requiring cardioversion or defibrillation, no left ventricular (LV) dysfunction (LV ejection fraction ≥50%), and intact coronary arteries (no coronary stenosis >50%) were included. In contrast, patients with known causes of cardiac arrest (n = 5), including ECG diagnosis of LQTS (resting QTc >460 ms in men and 480 ms in women) or Brugada syndrome, hypertrophic cardiomyopathy, marked hypokalemia, and drug overdose, were excluded. Genetic testing, which was approved by the local ethics committee, was performed on all the study patients (minutes no. 2 of the meeting of the Bioethics Committee of the Institute of Genetics and Cytology of the National Academy of Sciences of Belarus, dated June 8, 2021). All patients signed a voluntary informed consent to participate in the study.

Clinical and instrumental studies included a resting 12-lead ECG using the Intercard-3 recorder (Republic of Belarus), transthoracic echocardiography (TTE) using the IE-33 ultrasound system (Philips, USA), X-ray selective coronary angiography using Innova 3100 (General Electric, USA) and Siemens Artis Zee Cath/Angio System (Siemens, USA), or coronary CT scan (Siemens Somatom Force, Germany). Patients who met the enrollment criteria underwent further testing, including 24-hour Holter monitoring using Philips Zimed (Austria) and Oxford Medilog AR12 (UK) recorders, 2D Speckle Tracking TTE using Vivid 7 premium cardiac ultrasound system (General Electric, USA), and cardiac magnetic resonance imaging (MRI) using Magnetom Aera 1.5 T tomograph (Siemens, Germany) according to recent recommendations.

Mutations in the coding sequences of genes associated with channelopathies and other inherited cardiac arrhythmias were evaluated with high-throughput next-generation sequencing (NGS) using a MiSeq Gene Analyzer (Illumina, USA). Samples were prepared with the TruSight Cardio Sequencing Kit (Illumina, USA), which contains 174 genes associated with inherited cardiovascular diseases. Annotation of the sequencing results was conducted using the ANNOVAR software [14]. The clinical significance of new and previously described genetic variants was evaluated according to the 2015 ACMG recommendations. [15]. The following factors were considered: the prevalence of the identified genetic variant in large population samples (Genome Aggregation Database [GnomAD]), localization in the gene and variant type, prediction of pathogenicity in silico, assessment of pathogenicity status in genetic databases (ClinVar, HGMD) and in peer-reviewed literature, availability of functional studies, and analysis of cascade screening data to elucidate variant segregation with disease within a family. Genetic variants classified as pathogenic (class V) and likely pathogenic (class IV) were considered diagnostically significant. Additionally, variants of uncertain significance (VUS; class III), which were predicted to be pathogenic in silico and whose frequency of occurrence in population databases (GnomaD) did not exceed 0.01%, were analyzed.

Statistical analysis was conducted using the StatSoft Statistica version 12.0 package and Microsoft Excel 2021. The quantitative data were represented by the median and quartiles in the form of Me [LQ; UQ], whereas the qualitative data were described by absolute values and percentages (n [%]).

RESULTS

Overall, 20 patients (10 women, 10 men; median age: 36 [28; 44] years) who had UCA caused by IVF and underwent resuscitation and ICD implantation were studied. Among the patients, 16 (80%) had a history of syncope. Moreover, 4 (20%) patients had close relatives with SCD (Table 1). The patients’ clinical and instrumental characteristics are presented in Table 2.

 

Table 1. Clinical and genetic characteristics of patients with idiopathic ventricular fibrillation

Patient code	Age	Sex	Family history of SCD	History of syncope	QTc max	Gene (variant class)	Clarified diagnosis	Events/outcomes
873с	48	female	–	+	530	KCNH2 (III–IV)	LQTS2	VF, CPR, ICD
829	44	female	–	+	380	AKAP9 (III)	LQTS11	VF, CPR, ICD
586	33	male	–	+	445	ANK2 (III)	LQTS4	VF, CPR, ICD
543	45	male	–	+	375	ANK2 (III)	LQTS4	Recurrent VT/VF, ICD, electrical storms
15м	29	male	–	–	323	KCNQ1 (III)	SQTS	VF, CPR, ICD
732	55	female	–	+	430	SCN10A (III)	BrS	VF, ICD
799	41	male	+	+	420	SCN5A (V) JUP (III)	BrS	VF, ICD
642с	15	male	–	+	450	RYR2 (IV–V)	CPVT	VT/VF, CPR, ICD
590	21	male	–	–	374	CACNA1C (III)	IVF	VF, CPR, ICD
816	19	male	+	–	380	RBM20 (IV) MYH7 (III)	NDLVC	VF/EC
868с	36	female	–	+	410	KCNH5 (III) JPH2 (III)	IVF	VF, EC, ICD
644	46	female	–	+	460	not detected	IVF	VT/VF, ICD
647	46	male	–	+	477	not detected	IVF	VT/VF, ICD
629	40	female	–	+	478	not detected	IVF	VF, CPR, ICD
612	16	male	–	+	380	not detected	IVF	VF, CPR, ICD
729	44	female	–	+	405	not detected	IVF	VF, CPR, ICD
805	23	female	–	+	340	not detected	IVF	VF, CPR, ICD
574	30	female	+	+	450	not detected	IVF	VF, CPR, ICD
648с	36	female	+	+	448	not detected	IVF	VF, CPR, ICD
782	30	male	–	–	420	not detected	IVF	VF, CPR, ICD

Note: SCD — sudden cardiac death; VF — ventricular fibrillation; CPR — cardiopulmonary resuscitation; ICD — implantable cardioverter-defibrillator; VT — ventricular tachycardia; EC — electrical cardioversion; LQTS — long QT syndrome; SQTS — short QT syndrome; CPVT — catecholaminergic polymorphic ventricular tachycardia; IVF — idiopathic ventricular fibrillation; NDLVC — non-dilated left ventricular cardiomyopathy; BrS — Brugada syndrome.

 

Table 2. Clinical and instrumental characteristics of patients with unexplained cardiac arrest

Parameters	Group of patients with UCA (n = 20)
Clinical parameters
Age at diagnosis, years, Ме [LQ; UQ]	36 [28; 44]
Age of disease manifestation, years, Ме [LQ; UQ]	35 [27; 41]
Gender, n (%) Female Male	10 (50) 10 (50)
Family history of SCD, n (%)	4 (20)
Syncope, n (%)	16 (80)
Clinical phenotype, n (%) LQTS SQTS Brugada syndrome CPVT NDLVC IVF	4 (20) 1 (5) 2 (10) 1 (5) 1 (5) 11 (55)
QTc max, Ме [LQ; UQ]	420 [380; 450]
TTE parameters
LV EF, %, Ме [LQ; UQ]	58 [56; 63]
LAVI, mL/m2,Ме [LQ; UQ]	34 [30; 38]
LV EDD, mm, Ме [LQ; UQ]	50 [48; 53]
LV ESD, mm, Ме [LQ; UQ]	31 [30; 34]
LV EDV, mL, Ме [LQ; UQ]	112 [106; 135]
LV ESV, mL, Ме [LQ; UQ]	49 [36; 56]
PASP, mmHg, Ме [LQ; UQ]	21 [20; 23]

Note: UCA — unexplained cardiac arrest; SCD — sudden cardiac death; LQTS — long QT syndrome; SQTS — short QT syndrome; CPVT — catecholaminergic polymorphic ventricular tachycardia; IVF — idiopathic ventricular fibrillation; NDLVC — non-dilated left ventricular cardiomyopathy; QTc — corrected QT interval; TTE — transthoracic echocardiography; LV EF — left ventricular ejection fraction; LAVI — left atrium volume index; LV EDD — left ventricular end-diastolic diameter; LV ESD — left ventricular end-systolic diameter; LV EDV — left ventricular end-diastolic volume; LV ESV — left ventricular end-systolic volume; PASP — pulmonary artery systolic pressure.

 

Genotyping by NGS revealed likely pathogenic variants in 4 (20%) patients (Table 3). In 7 (35%) probands, variants of unknown clinical significance (pathogenicity class III) were detected in 10 genes associated with channelopathies (KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, SCN10A, and RYR2) and cardiomyopathies (MYH7, JPH2, and RBM20). A combination of several genetic variants was found in three patients. No significant genetic changes were determined in 9 (45%) of 20 probands. Clinical diagnosis was established during the follow-up period by comprehensive examination and confirmed by genetic testing in 5 (25%) patients (codes 873c, 15m, 732, 799, and 642). Serial ECGs showed QTc interval prolongation >480 ms in one patient (code 873c), Brugada pattern in two patients (codes 732 and 799), and QTc interval shortening up to 323 ms in one patient (code 15m). Subclinical structural changes associated with cardiomyopathies were identified in two patients (codes 816 and 868c). In 15 (75%) patients, no clear clinical phenotype was established (codes 829, 586, 543, 642с, 590, 868c, 644, 647, 629, 612, 729, 805, 574, 648c, and 782). In 6 (30%) patients (codes 829, 586, 543, 642с, 590, and 868c), the diagnosis was clarified using the genetic variants detected.

LQTS-related genetic alterations were prevalent among patients with UCA caused by VF, occurring in 30% of cases. Proband 873c (female, 48 years old) exhibited QTc prolongation caused by a variant in the KCNH2 gene (Fig. 1). The disease manifested at age 48 years with cardiac arrest, which was treated with resuscitation and subsequent ICD implantation. A series of ECGs obtained over the past year demonstrated no alterations in T wave morphology or QTc prolongation (420–440 ms). An ECG performed a year ago exhibited QTc prolongation of up to 482 ms. The patient had been suffering from syncope and presyncope for approximately 3 years. Based on the genotyping data, LQTS type 2 was diagnosed.

 

Fig. 1. 12-lead ECG of proband 873c. Prolonged QTc interval — 482 ms, ventricular premature beat (red ellipse)

 

VUS in exons 15 and 38 of the ANK2 gene, which encodes the adaptor protein ankyrin-B, were identified in two unrelated male probands (codes 543 and 586). Both patients exhibited no aggravated family history and demonstrated QTc interval prolongation on ECG series (median QTc: 407.5 [375; 440] ms). Prior to the onset of VF, the patients experienced recurrent syncope requiring CPR and ICD implantation. Patient 543 (male, 43 years old) who had a p.Thr466Met substitution in the ANK2 gene developed polymorphic VT/VF controlled by an ICD multiple times during the 8-year follow-up, which led to ICD replacement 3 times. During the last 2 years, no recurrences of syncopal episodes and multiple ICD storms requiring CPR were noted. Considering the results of genotyping, the patients were diagnosed with IVF probably caused by mutations in the ankyrin gene.

In proband 829 (female, 44 years old) who showed a novel variant in the AKAP9 gene, no family history of SCD and no QT interval prolongation on serial ECGs were recorded. The disease manifested at age 44 years with cardiac arrest caused by VF, which required CPR and ICD implantation. Frequent premature ventricular contractions and sustained and nonsustained paroxysms of VT were recorded during 24-hour Holter monitoring (Fig. 2). A comprehensive examination showed no structural myocardial abnormalities. Considering the genotyping data, VF was diagnosed due to the variant in the AKAP9 gene. However, subsequent cascade screening of the proband’s son (32 years old) and daughter (25 years old) using Sanger sequencing did not establish the pathogenic significance of the new variant, because both children were carriers of the same c.8747C>T substitution in the AKAP9 gene, but had no ECG alterations and no other clinical manifestations. Owing to the incomplete penetrance of the disease and pathogenicity of the variant according to in silico prognostic predictors, regular follow-up with a cardiologist was recommended.

 

Fig. 2. 24-hour Holter ECG of patient 829. Ventricular premature beats and paroxysms of nonsustained ventricular tachycardia

 

Cardiac arrest due to IVF and subsequent ICD implantation were recorded in four genotype-negative patients (codes 644, 647, 629, and 574) with borderline QTc values on ECG (median 465 [460; 477]). Moreover, two of the patients had a family history of SCD, indicating a hereditary nature of the disease (Table 1).

In 2 (10%) patients, the disease manifested with the development of IVF following CPR and ICD implantation; a Brugada pattern was detected on ECG at follow-up. Proband 799 (male, 41 years old) had a family history of SCD; his father died from SCD at age 28 years (Fig. 3). The proband experienced syncopal episodes unrelated to physical activity during the day and, eventually, cardiac arrest developed at night. ECG showed a spontaneous Brugada type 1 pattern. Hereinafter, no Brugada pattern was observed, and sinus rhythm with HR at 68 beats/min, PQ interval duration at 110 ms, QTc interval at 380 ms, and QRS at 120 ms was recorded. Genotyping revealed a likely pathogenic variant p.Glu48Lys in the SCN5A gene and an additional substitution in the JUP gene associated with arrhythmogenic right ventricular cardiomyopathy (ARVC).

 

Fig. 3. Pedigree of the proband 799’s family with mutations p.Glu48Lys in SCN5A gene and p.Ala143Thr in JUP gene. The proband is indicated by an arrow. Clinically affected individuals are indicated by the shaded symbols

 

Cardiac MRI showed no structural myocardial changes nor evidence of ARVC. Considering the genotyping data, Brugada syndrome was diagnosed. Cascade screening in the proband’s younger brother (31 years old) and daughter (10 years old) revealed a variant in the SCN5A gene. Neither had a substitution in the JUP gene, herewith the daughter having syncopal episodes and the younger brother being asymptomatic.

Patient 732 (female, 55 years old, no family history of SCD) who was admitted to the intensive care unit with cardiac arrest had a recorded VF and was subsequently implanted with an ICD. ECG showed a Brugada type 1 pattern (Fig. 4). Genotyping revealed a p.Asp1739Val substitution in the SCN10A gene encoding a neuronal sodium channel (Nav1.8), which has been associated with Brugada syndrome in recent whole-genome association studies. Phenotypic similarities have been demonstrated between patients with a SCN10A gene variant and SCN5A gene variants, including family history, presence of syncope, and spontaneous ECG pattern [16].

 

Fig. 4. 12-lead ECG of patient 732 with Brugada pattern type 1 (“coved”), showing a “vaulted” ST elevation of more than 2 mm in V1–V2, followed by a negative T-wave

 

In patient 642c (male, 15 years old), the disease manifested at age 15 years with the development of cardiac arrest caused by polymorphic VT/VF (Fig. 5). CPR was performed, and a ICD was implanted for secondary prevention of SCD. Genotyping revealed a pathogenic mutation, c.14876G > A (p.Arg4959Gln, rs794728811), in the RYR2 gene. Based on these results, CPVT was diagnosed. The mother of the proband was found to have the same mutation, which manifested clinically as presyncope and palpitations.

 

Fig. 5. 24-hour Holter ECG of patient 642с. Ventricular premature beat, R on T pattern (red asterisk), initiated a paroxysm of ventricular tachycardia with transformation into ventricular fibrillation

 

In patient 590 (male, 21 years old), a comprehensive clinical examination following cardiac arrest and resuscitation with subsequent ICD implantation revealed no structural abnormalities or ECG alterations. Genotyping identified a CACNA1C gene variant, which encodes the L-type calcium channel alpha subunit (CAV1.2). This variant is associated with channelopathies, namely, Timothy syndrome. However, no changes were detected on ECG, and no indications of syndactyly, cognitive impairment, facial dysmorphism, or other noncardiac characteristics suggestive of Timothy syndrome were observed.

Notably, variants in genes associated with the development of cardiomyopathy were detected in two patients with IVF. In patient 816 (male, 19 years old), who exhibited no myocardial structural abnormalities at the time of examination, variants in the RBM20 and MYH7 genes associated with various cardiomyopathies, including the dilated cardiomyopathy or non-dilated left ventricular cardiomyopathy (NDLVC) phenotype, were detected on TTE and cardiac MRI. The patient had no obvious clinical phenotype during VF. A family history of SCD was noted; his mother developed the disease at age 33 years. At 2-year follow-up, 2D-Strain TTE showed a moderate decrease in global longitudinal strain (–13.6%) (Fig. 6), with no LV dilatation, confirming cardiomyopathy. Thus, the diagnosis of IVF was changed to NDLVC. In patient 868c (female, 36 years old), in the absence of myocardial structural abnormalities, variants in JPH2 genes associated with cardiomyopathies and in KCNA5 associated with familial atrial fibrillation were detected on TTE and cardiac MRI. No alterations of T wave morphology or prolonged QTc interval (QTc: 420–440 ms) were observed on ECG. No atrial fibrillation was determined in the patient’s medical history or during 24-hour Holter monitoring. Moreover, no evidence of cardiomyopathy or cardiac channelopathy was found in the patient’s family history. Currently, subclinical structural myocardial abnormalities are suspected in the patient, and further follow-up is required to confirm the diagnosis.

 

Fig. 6. 2D Speckle Tracking Echocardiography of patient 816. Left ventricular global longitudinal strain — 13,6 %

 

In a group of 20 patients with UCA and VF, the clinical phenotype was linked to genetic variants in 11 (55%) patients, as indicated by the presence of one of the following variants: 873c, 829, 586, 543, 15m, 732, 799, 642с, 816, 868c, and 590. Pathogenic variants were identified in genes associated with LQTS, SQTS, Brugada syndrome, CPVT, and subclinical manifestations of various cardiomyopathies.

DISCUSSION

In the present study, among 20 patients initially diagnosed with IVF and UCA, the clinical diagnosis of IVF was clarified in 11 (55%) patients by genetic testing. It revealed likely pathogenic variants in the KCNH2, SCN5A, RYR2, and RBM20 genes in 4 (20%) patients. In 7 (35%) patients, variants of unknown clinical significance were found in 10 genes associated with channelopathies and cardiomyopathies. No significant genetic alterations were detected in 9 (45%) out of 20 probands, although 4 had borderline QTc values on ECG and 2 had a family history of SCD. Apparently, the absence of genetic disorders in these patients may be due to the localization of diagnostically significant mutations in introns or in other genes not included in the research panel, or extensive deletions, the detection of which by the NGS method is challenging.

Genetic alterations associated with LQTS (30%) were common in patients with UCA, with only one patient exhibiting a mutation in the KCNH2 gene having QTc prolongation up to 500 ms on one ECG series. In other patients with substitutions in the ANK2 gene and a mutation in the AKAP9 gene, the QTc interval was ≤ 440 ms. Furthermore, the pathogenic mutation in the CACNA1C gene was not associated with QTc prolongation and other noncardiac manifestations suggestive of Timothy syndrome. Therefore, without genotyping, early diagnosis before the development of a life-threatening arrhythmic event is challenging.

The clinical phenotype of CPVT in proband 642 before age 15 years was not manifested by polymorphic nonsustained VT characteristic of this pathology, which is triggered by physical activity or emotion. Genetic testing after the development of the event revealed a mutation in the RYR2 gene, which allowed the diagnosis to be changed to CPVT.

In two patients in whom the disease manifested with the development of VF, genotyping revealed a likely pathogenic variant in the SCN5A gene and substitution in the SCN10A gene. The spontaneous Brugada pattern was recorded on ECG at the time of the arrhythmic event with no further signs of this disorder on serial ECGs. Owing to genetic study, the diagnosis of IVF was changed to Brugada syndrome.

It is noteworthy that genotyping of patients with IVF revealed genetic variants associated with cardiomyopathies; however, the patients exhibited no obvious clinical phenotype during VF.

The results of genetic testing in patients who had UCA showed a pathogenic or likely pathogenic variant in 20% of cases. These findings demonstrate that a genetic heart disease can manifest as a life-threatening arrhythmia even in the absence of a clear clinical phenotype. Therefore, genetic testing is crucial in patients who have had UCA/IVF. The identification of a clinical phenotype in genotyped probands facilitates detection of more pathogenic variants. This is due to genetic alterations identified in the patient allow for cascade screening of family members, during which segregation analysis may confirm the pathogenicity of some variants with unknown clinical significance. Conversely, in patients without an identifiable clinical phenotype, the test results may remain negative [17].

However, VUS remain a challenging problem in clinical practice, requiring considerable time, resources, and experience to resolve [18]. In our research, VUS were detected in 7 (35%) patients. Studies on molecular autopsy using large gene panels in investigating sudden arrhythmic death syndrome, which can be considered equivalent to UCA/IVF, showed comparable results. Nunn et al. reported that in a set of 135 genes in 59 patients with sudden arrhythmic death syndrome, 29% of patients had likely pathogenic variants and 34% had VUS [19]. Bagnall et al. reported a 27% efficiency when testing 59 genes in 113 cases of unexplained SCD [20].

Our results indicate that genetic testing is recommended for all patients with UCA, with or without evidence of cardiovascular disease. Long-term prospective studies with a large cohort of genotyped UCA patients and their families are required to determine the potential role of genetic variants in risk stratification. A better understanding of genotype–phenotype association is favorable in determining the contribution of VUS and identifying more reliable criteria for assessing pathogenicity.

CONCLUSIONS

The data from our study are intended to convey that cardiac channelopathies and subclinical manifestations of cardiomyopathies are common causes of disease in IVF patients with UCA, which require genetic testing in this group of patients. Genotyping of UCA patients revealed genetic changes associated with LQTS in 30% of cases. The QTc interval did not exceed 440 ms in most cases, making early diagnosis before the development of a life-threatening arrhythmic event challenging. Identifying the underlying genetic variant responsible for cardiac arrest may be beneficial in clarifying the clinical diagnosis, providing individualized treatment, and facilitating cascade screening of other at-risk family members.

STUDY LIMITATIONS

This study had several limitations. Firstly, the study sample was relatively small. Secondly, the final cohort included only patients who survived UCA referred for genetic testing. Finally, the lack of the clinical and genetic data of family members prevents a more precise interpretation of the impact of the identified variants, including those of unknown clinical significance.

ADDITIONAL INFORMATION

Ethics approval. The protocol of the study was approved by Institute of Genetics and Cytology of Belarus National Academy of Sciences Ethics Committee, protocol No. 2, 08.06.2021. Written consent was obtained from the patient for publication of relevant medical information and all accompanying images within the manuscript.

Author contribution. Thereby, all authors confirm that their authorship complies with the international ICMJE criteria (all authors have made a significant contribution to the development of the concept, research, and preparation of the article, as well as read and approved the final version before its publication). Personal contribution of the authors: S.M. Komissarova — concept and design of the study, writing — original draft, patient follow-up; N.N. Chakova — conducting and interpreting the results of genetic analysis, writing — original draft; N.M. Rineiska — data curation, diagnostic studies, writing — original draft, review and editing, literature review; S.S. Niyazova — conducting and interpreting the results of the genetic analysis; T.V. Dolmatovich — conducting and interpreting the results of the genetic analysis; V.Ch. Barsukevich — patient follow-up; L.I. Plaschinskaya — diagnostic studies.

Competing interests. The authors declare that they have no competing interests.

Funding source. This study was not supported by any external sources of funding.

ДОПОЛНИТЕЛЬНАЯ ИНФОРМАЦИЯ

Заключение этического комитета. Протокол исследования был одобрен этическим комитетом Института генетики и цитологии Национальной академии наук Беларуси (протокол № 2 заседания Комитета по биоэтике от 08.06.2021). Авторы получили письменное согласие законных представителей пациентов на публикацию медицинских данных и фотографий.

Вклад авторов. Все авторы внесли существенный вклад в разработку концепции, проведение исследования и подготовку статьи, прочли и одобрили финальную версию перед публикацией. Вклад каждого автора: С.М. Комиссарова — концепция и дизайн исследования, написание текста, динамическое наблюдение за пациентами; Н.Н. Чакова — проведение и интерпретация результатов генетического анализа пациентов, написание текста; Н.М. Ринейская — анализ полученных данных, диагностические исследования, написание текста, обзор литературы; С.С. Ниязова — проведение и интерпретация результатов генетического анализа пациентов; Т.В. Долматович — проведение и интерпретация результатов генетического анализа пациентов; В.Ч. Барсукевич — динамическое наблюдение за пациентами; Л.И. Плащинская — диагностические исследования.

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи.

Источник финансирования. Авторы заявляют об отсутствии внешнего финансирования при проведении исследования.

About the authors

Svetlana M. Komissarova

“Cardiology” State Institution Republican Scientific and Practical Centre

Email: kom_svet@mail.ru
ORCID iD: 0000-0001-9917-5932
SPIN-code: 8023-5308

MD, Dr. Sci. (Med.), professor

Belarus, Minsk

Natalya N. Chakova

Institute of Genetics and Cytology of Belarus National Academy of Sciences

Email: chaknat@mail.ru
ORCID iD: 0000-0003-4721-9109
SPIN-code: 5682-1497

Cand. Sci. (Biol.)

Belarus, Minsk

Nadiia M. Rineiska

“Cardiology” State Institution Republican Scientific and Practical Centre

Author for correspondence.
Email: nadya.rin@gmail.com
ORCID iD: 0000-0002-1986-1367
SPIN-code: 2782-2270

MD, Cand. Sci. (Med.), researcher, Laboratory of Chronic Heart Failure

Belarus, Minsk

Svetlana S. Niyazova

Institute of Genetics and Cytology of Belarus National Academy of Sciences

Email: kruglenko_sveta@tut.by
ORCID iD: 0000-0002-3566-7644
SPIN-code: 1093-1793

junior researcher

Belarus, Minsk

Tatyana V. Dolmatovich

Institute of Genetics and Cytology of Belarus National Academy of Sciences

Email: t.dolmatovich@igc.by
ORCID iD: 0000-0001-7562-131X

Cand. Sci. (Biol.)

Belarus, Minsk

Veronika Ch. Barsukevich

“Cardiology” State Institution Republican Scientific and Practical Centre

Email: barsukevich.v@gmail.com
ORCID iD: 0000-0002-5180-7950
SPIN-code: 9413-7121

MD, Cand. Sci. (Med.)

Belarus, Minsk

Larisa I. Plashchinskaya

“Cardiology” State Institution Republican Scientific and Practical Centre

Email: lario2001@mail.ru
ORCID iD: 0000-0001-8815-3543
SPIN-code: 2666-1270

MD, Cand. Sci. (Med.)

Belarus, Minsk

References

Supplementary files