Next Article in Journal
Angiotensin II Receptor Blocker Irbesartan Enhanced SIRT1 longevity Signaling Replaces the Mitochondrial Biogenetic Survival Pathway to Attenuate Hypertension-Induced Heart Apoptosis
Previous Article in Journal
Overcoming High Impedance in the Transitional Area of the Distal Great Cardiac Vein during Radiofrequency Catheter Ablation of Ventricular Arrhythmia
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCDD
Volume 9
Issue 8
10.3390/jcdd9080265
jcdd-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Genetic Analysis of Cardiac Syncope-Related Genes in Korean Patients with Recurrent Neurally Mediated Syncope

by
Sung Ho Lee
1,†,
Jong Eun Park
2,†,
Chang-Seok Ki
3,
Seung-Jung Park
4,
Young Keun On
4,
Kyoung-Min Park
4,* and
June Soo Kim
4,*
1
Division of Cardiology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Korea
2
Department of Laboratory Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Korea
3
GC Genome, Yongin 16924, Korea
4
Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Cardiovasc. Dev. Dis. 2022, 9(8), 265; https://doi.org/10.3390/jcdd9080265
Submission received: 30 June 2022 / Revised: 9 August 2022 / Accepted: 11 August 2022 / Published: 14 August 2022
(This article belongs to the Section Genetics)
Versions Notes

Abstract

:
Neurally mediated syncope (NMS) is a common clinical problem. The underlying genetic factors of NMS remain controversial. We hypothesized that cardiac syncope-related genes may contribute to NMS in patients with previous frequent syncopal episodes and/or a family history of syncope. A total of 54 consecutive patients diagnosed with NMS were prospectively enrolled between 2013 and 2016. Inclusion criteria were more than five syncopal episodes with a family history of syncope (n = 17) or more than five syncopal episodes with no family history of syncope (n = 37). Ninety-eight cardiac syncope-related genes (channelopathy: 43 genes, cardiomyopathy: 50 genes, primary pulmonary hypertension: 5 genes) were screened by exome sequencing. All identified variants were classified according to the standards and guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Of the 54 patients, 17 patients (31.5%) had a family history of syncope. Two patients (3.7%) had pathogenic and likely pathogenic variants (PV/LPV) in cardiac syncope-related genes TTN and MYH7. We investigated genetic variation in patients with frequent NMS with a positive family history of syncope in Korea. PV/LPVs in genes related to cardiomyopathy were associated with recurrent NMS in Korean patients. Closer follow-up of these patients might be needed.

1. Introduction

Neurally mediated syncope (NMS) is a common clinical problem that occurs in about 25% of the general population [1,2]. The mechanism of NMS remains unclear, but some researchers have suggested a genetic cause based on some familial forms of NMS [3,4,5,6]. Previous studies reported a frequency in family history of NMS from 19% to 50% [4,7,8]. Twin and familial studies revealed that NMS shows an autosomal dominant pattern [6]. Based on such a strong family history of syncope, some authors suggested a genetic involvement in the pathophysiological cascade leading to syncope [7,9]. In Western studies, an association between the cause of NMS and various single-nucleotide polymorphisms (SNPs) in sympathetic activity-related genes was suggested [9,10,11,12,13,14,15,16,17,18]; however, the genetic factors associated with NMS have not been elucidated and the results thus far have been conflicting [7,19,20]. There are many difficulties in explaining the cause of NMS based only on SNPs. The causes of syncope are diverse; some syncope may be associated with cardiac structural disease or channelopathy and the consequent increased risk of death [21]. It is important to identify the cause of syncope to establish an effective therapy. In this study, we hypothesized that cardiac syncope-related genes may contribute to NMS in patients with previous frequent syncopal episodes and/or a family history of syncope.

2. Materials and Methods

2.1. Study Population

A total of 150 consecutive patients with recurrent NMS were prospectively enrolled between March 2013 and September 2016. The diagnosis of NMS was made based on the clinical history and confirmed by a head-up tilt test and negative cardiologic evaluation (12-lead electrocardiogram, 24-h Holter, treadmill test, echocardiogram). All patients had experienced at least one episode of syncope within the 12 months before enrollment. Patients were free from any structural heart disease, arrhythmia, diabetes mellitus, or neurologic disease and were not taking any medication affecting autonomic function. Height and body weight were measured by trained staff. Body mass index was calculated as the weight in kilograms divided by the height in meters squared. Systolic blood pressure, diastolic blood pressure and heart rate at rest were measured. Questionnaires were used to determine current medication, and underlying diseases including cardiovascular disease, the number of previous syncopal or pre-syncopal episodes, triggering factors, seizure-like activity during syncope, syncope-related physical injury, prodromal symptoms, and presence or absence of a family history of syncope. Patients also provided information on syncope in first-degree and second-degree relatives. Among the total patient group, patients with frequent NMS were included in this study if they suffered more than 5 previous syncopal episodes (n = 37) or if they suffered more than 5 syncopal episodes and had a family history of syncope (n = 17). The study was approved by the regional Ethical Committee of the Samsung Medical Center (IRB No. 2012-11-005) and followed the Declaration of Helsinki. Informed consent was obtained from the study participants.

2.2. Whole-Exome Sequencing

Genomic DNA was extracted from peripheral blood leukocytes using a Wizard Genomic DNA purification kit (Promega, Madison, WI, USA) according to the manufacturer’s instructions. SureSelect Human All Exon V5 (Agilent Technologies, Santa Clara, CA, USA) was used for library preparation; sequencing was performed using the Illumina HiSeq2500 platform (Illumina Inc., San Diego, CA, USA). Alignment of the sequence reads was performed against the Human Reference Genome build GRCh37 using BWA 0.7.12; duplicated reads were marked with Picard Tools 1.130; the local alignment, base quality recalibration and variant calling were performed with the Genome Analysis Tool Kit v3.4.0; and annotation and variant effect prediction were performed with SnpEff v4.1g.

2.3. Variant Filtering Steps and Interpretation of Candidate Variants

The called variants were filtered and prioritized using a four-step strategy to generate a short candidate variant list for experimental validation (see Supplementary File S1: Figure S1). We first removed variants below 10× coverage. Variants were then limited to those with a low population frequency. Before removing <10× variants, we checked against ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/, accessed on 5 April 2019) and the Human Gene Mutation Database (HGMD, http://www.hgmd.org/, accessed on 29 June 2022). Any previously reported pathogenic or probable pathogenic variants, whether or not these variants were <10×, were not filtered out. The minor allele frequency (MAF) threshold was carefully chosen and variants less than 0.01 were identified in the Genome Aggregation Database (gnomAD) (http://gnomad.broadinstitute.org/, accessed on 29 June 2022) or the Korean Reference Genome Database (KRGDB) (http://152.99.75.168/KRGDB, accessed on 29 June 2022). The next step was to include the variants predicted to have a high impact on protein function, including missense, nonsense, frameshifts, in-frame insertions/deletions variants, or changes affecting the consensus splice site sequences. Finally, we performed a gene-specific analysis with an in silico gene panel composed of 98 cardiac syncope-related genes (channelopathy: 43 genes, cardiomyopathy: 50 genes, primary pulmonary hypertension: 5 genes) (Table 1). These genes were obtained by searching previous publications [22,23].
Candidate variants were classified according to the standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) [24]. These guidelines recommend classifying variants into five categories: pathogenic variant (PV), likely pathogenic variant (LPV), variant of uncertain significance (VUS), likely benign variant, and benign variant based on the combination of many lines of weighted evidence. The MYH7 gene, with ClinGen’s inherited cardiomyopathy expert panel recommendation, was additionally reflected when interpreting the ACMG/AMP guidelines [25]. To assess the frequency of a variant in the control or general population, we used the gnomAD, which consists of 125,748 exomes and 4359 genomes, and the KRGDB, which consists of 1722 Korean genomes. A primary literature review was conducted using various sources cited in the HGMD professional version (release February 2018), ClinVar, and PubMed to determine the potential pathogenicity of all identified variants. A variety of in silico tools were used to assess the predicted impact of missense change, including SIFT (http://sift.jcvi.org, accessed on 29 June 2022) and Polyphen2 (http://genetics.bwh.harvard.edu/pph2, accessed on 29 June 2022).

3. Results

3.1. Patient Characteristics

Clinical characteristics are shown in Table 2. Among the 54 patients, 36 (66.7%) were female; the mean patient age was 41.3 ± 8.9 years. The median number of previous syncopal episodes was six (interquartile range, 5–10). A total of 17 patients (31.5%) had a family history of syncope. The most common relative with a family history of syncope was the patient’s mother (24.1%), followed by sister (7.4%), aunt (3.7%) and son (1.9%). There was no history of syncope in relatives on the paternal side (patient’s father or brother).
Major syncope-related injuries, such as tooth fracture, were observed in two patients (3.7%); minor injuries such as contusions or lacerations were reported in thirty-one patients (57.4%). Thirty-five (64.8%) patients were classified as vasodepressive type, eleven (20.4%) patients as mixed type, and seven (13.0) patients as cardioinhibitory type according to Vasovagal Syncope International Study classification [26].

3.2. Genetic Characteristics of Subjects

Of the fifty-four patients, two patients (3.9%) had PV/LPVs according to the 2015 ACMG/AMP guidelines (Table 3). PVs were identified in MYH7 and LPVs in TTN. A total of 113 VUSs were also identified (see Supplementary File S1: Tables S1–S3).
In a 34-year-old woman (PT-001) who had a family history of syncope involving her mother and sister and experienced syncope 10 times, an LPV (c.27755_27756insTCTTCTTTGTATG; p.Thr9253Leufs*23) was identified in the TTN gene; this is a novel variant that was absent from the control database. This variant was classified as an LPV with PVS1 and PM2 evidence. TTN can cause dilated cardiomyopathy (DCM) and a heterozygous truncated variant is the most common genetic cause of familial DCM [27].
In a 44-year-old woman (PT-104) who had a family history of syncope involving her son and experienced syncope five times, a PV (c.2608C>T;p.Arg870Cys) was identified in the MYH7 gene. This PV was observed in an East Asian control (MAF of 0.006% in the gnomAD East Asian) and previously reported in familial hypertrophic cardiomyopathy (HCM) [28]. This variant was classified as a PV with PS4, PM1, PM2, PM5, and PP3 evidence. The MYH7 gene is one of the major causative genes of HCM. According to Woo et al., a family affected by p.Arg870Cys had three premature cardiac deaths and one patient requiring myectomy among five family members.

4. Discussion

We analyzed 98 cardiac syncope-related genes in 54 patients with frequent recurrent NMS. Two PV/LPVs related to cardiomyopathy were detected in the TTN and MYH7 genes. A total of 113 VUSs were identified in the 54 patients.
Previous genetic studies on NMS focused on the genes involved in cardiovascular reflex and the autonomic nervous system, affecting heart rate and vasoconstriction [7,20]; however, conflicting results have been reported regarding the genetic factors involved in the autonomic system [16,18,20,29,30,31]. These diverse results may be due to different study designs and methodologies regarding genes, ethnic differences, and different statistical analyses and sample sizes. Before the era of whole-exome sequencing, studies on SNPs associated with NMS might have had many limitations. In genetic studies, the significance level is usually set much lower than statistical p value significance (<0.05) and the results often come out as irrelevant [32]. Because GWAS platforms focus on common SNPs, effect sizes are often small and difficult to identify and validate unless a very large number of subjects is examined. In addition, SNPs associated with traits are usually not functional but rather serve as markers for loci that harbor truly functional variants.
Interestingly, two patients (3.9%) had PV/LPVs in the TTN and MYH7 genes. TTN truncating variants have been suggested to cause 25% of DCM [27], and the MYH7 gene, related to sarcomeres, may be present with a spectrum of phenotypical cardiomyopathies [HCM, DCM]) [33,34]. Although the patients in question had no clinical manifestations of cardiomyopathy, it would be considered carefully to extend surveillance of cardiomyopathy with electrocardiography or cardiac imaging to detect the development of phenotypically expressed cardiomyopathy [35]. However, there was also no family history of cardiomyopathy among their relatives.
Syncope might be the first manifestation of HCM in asymptomatic patients in the absence of LV hypertrophy on an echocardiogram [36]. Approximately 20% of HCM patients show a normal or near-normal LV mass on cardiac magnetic resonance imaging as a result of localized hypertrophy [37], and early stage HCM might not be diagnosed on conventional examinations. Thus, cardiomyopathy related syncope may be regarded as benign NMS because there is no evidence of structural and electrical abnormalities on conventional diagnostic examinations, or it might not be distinguished if there are combined overlapping NMS clinical features. Genetic testing could be an option for detecting early-stage cardiomyopathy. Follow-up of these genetic variant-related cardiomyopathy syncope patients over regular intervals with electrocardiography or imaging modalities such as echocardiography is critical to determine whether a cardiomyopathy phenotype will develop. Therefore, prolonged careful observation of these patients might be needed.
Our study has several limitations. First, the clear genetic causes of NMS are still unknown. Therefore, in this study, we had limitations in analyzing genes that were associated with NMS. NMS is also affected by environmental factors. Thus, gene-environment interactions could affect the predisposition to NMS. Second, a number of cardiomyopathy genes were found in a few patients, and cardiomyopathy-related genes themselves might not have clinical significance without the phenotype. Third, the study population sample size was relatively small. Further studies with more patients are needed. Lastly, family history data for syncope were self-reported by the patients. It is possible these patients may not be aware of every family member who suffered syncope and the number of affected family members may thus be underestimated. However, the unique point of this study is that we analyzed cardiac syncope-related genes among NMS patients with previous syncopal episodes and/or a family history of syncope and we found identified pathogenic variants for cardiomyopathy in these recurrent NMS patients.
In conclusion, we investigated genetic variation in patients with frequent NMS with a positive family history of syncope in Korea. PV/LPVs in genes related to cardiomyopathy were associated with recurrent NMS in Korean patients. Whole-exome sequencing provides information to facilitate genetic diagnosis and personalized treatment.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcdd9080265/s1, Figure S1: Generation process of a candidate variant list using a four-step strategy; Table S1: List of variants of uncertain significance on in silico analysis of channelopathy genes; Table S2: List of variants of uncertain significance on in silico analysis of cardiomyopathy genes; Table S3: List of variants of uncertain significance on in silico analysis of primary pulmonary hypertension genes.

Author Contributions

Conceptualization, J.S.K., K.-M.P. and C.-S.K.; methodology, J.E.P. and C.-S.K.; validation, S.-J.P. and Y.K.O.; formal analysis, S.H.L. and J.E.P.; writing—original draft preparation, S.H.L. and J.E.P.; writing—review and editing, J.S.K. and K.-M.P.; supervision, J.S.K. and K.-M.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Samsung Medical Center (IRB No. 2012-11-005).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

All genomic variants identified in this study are available in Table 3 and Supplemental File Tables S1–S3. The original sequencing and clinical datasets generated during the current study are not publicly available due to patient confidentiality but are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors have no conflict of interest to declare.

References

  1. Chen, L.Y.; Shen, W.K.; Mahoney, D.W.; Jacobsen, S.J.; Rodeheffer, R.J. Prevalence of syncope in a population aged more than 45 years. Am. J. Med. 2006, 119, 1088.e1–1088.e7. [Google Scholar] [CrossRef] [PubMed]
  2. Ganzeboom, K.S.; Mairuhu, G.; Reitsma, J.B.; Linzer, M.; Wieling, W.; van Dijk, N. Lifetime cumulative incidence of syncope in the general population: A study of 549 Dutch subjects aged 35–60 years. J. Cardiovasc. Electrophysiol. 2006, 17, 1172–1176. [Google Scholar] [CrossRef] [PubMed]
  3. Klein, K.M.; Xu, S.S.; Lawrence, K.; Fischer, A.; Berkovic, S.F. Evidence for genetic factors in vasovagal syncope: A twin-family study. Neurology 2012, 79, 561–565. [Google Scholar] [CrossRef] [PubMed]
  4. Newton, J.L.; Kenny, R.; Lawson, J.; Frearson, R.; Donaldson, P. Prevalence of family history in vasovagal syncope and haemodynamic response to head up tilt in first degree relatives: Preliminary data for the Newcastle cohort. Clin. Auton. Res. Off. J. Clin. Auton. Res. Soc. 2003, 13, 22–26. [Google Scholar] [CrossRef] [PubMed]
  5. Marquez, M.F.; Urias, K.I.; Hermosillo, A.G.; Jardon, J.L.; Iturralde, P.; Colin, L.; Nava, S.; Cardenas, M. Familial vasovagal syncope. Europace 2005, 7, 472–474. [Google Scholar] [CrossRef]
  6. Klein, K.M.; Bromhead, C.J.; Smith, K.R.; O’Callaghan, C.J.; Corcoran, S.J.; Heron, S.E.; Iona, X.; Hodgson, B.L.; McMahon, J.M.; Lawrence, K.M.; et al. Autosomal dominant vasovagal syncope: Clinical features and linkage to chromosome 15q26. Neurology 2013, 80, 1485–1493. [Google Scholar] [CrossRef]
  7. Holmegard, H.N.; Benn, M.; Mehlsen, J.; Haunso, S. Genetic variation in the parasympathetic signaling pathway in patients with reflex syncope. Genet. Mol. Res. GMR 2013, 12, 2601–2610. [Google Scholar] [CrossRef]
  8. Serletis, A.; Rose, S.; Sheldon, A.G.; Sheldon, R.S. Vasovagal syncope in medical students and their first-degree relatives. Eur. Heart J. 2006, 27, 1965–1970. [Google Scholar] [CrossRef]
  9. Wittwer, E.D.; Liu, Z.; Warner, N.D.; Schroeder, D.R.; Nadeau, A.M.; Allen, A.R.; Murillo, C.J.; Elvebak, R.L.; Aakre, B.M.; Eisenach, J.H. beta-1 and beta-2 adrenergic receptor polymorphism and association with cardiovascular response to orthostatic screening. Auton. Neurosci. Basic Clin. 2011, 164, 89–95. [Google Scholar] [CrossRef]
  10. Zelazowska, M.; Lelonek, M.; Fendler, W.; Pietrucha, T. Arg389Gly beta1-adrenergic receptor polymorphism and susceptibility to syncope during tilt test. Arch. Med. Sci. AMS 2014, 10, 240–245. [Google Scholar] [CrossRef]
  11. Lelonek, M.; Zelazowska, M.; Pietrucha, T. Genetic variation in gsalpha protein as a new indicator in screening test for vasovagal syncope. Circ. J. Off. J. Jpn. Circ. Soc. 2011, 75, 2182–2186. [Google Scholar]
  12. Huang, Y.J.; Zhou, Z.W.; Xu, M.; Ma, Q.W.; Yan, J.B.; Wang, J.Y.; Zhang, Q.Q.; Huang, M.; Bao, L. Alteration of gene expression profiling including GPR174 and GNG2 is associated with vasovagal syncope. Pediatr. Cardiol. 2015, 36, 475–480. [Google Scholar] [CrossRef] [PubMed]
  13. Evin, L.; Mitro, P.; Habalova, V.; Simurda, M.; Muller, E.; Murin, P. Beta 3 subunit of G-protein and its influence on autonomic nervous system in patients with vasovagal syncope. Bratisl. Lek. Listy 2016, 117, 142–147. [Google Scholar] [CrossRef] [PubMed]
  14. Komiyama, T.; Hirokawa, T.; Sato, K.; Oka, A.; Kamiguchi, H.; Nagata, E.; Sakura, H.; Otsuka, K.; Kobayashi, H. Relationship between human evolution and neurally mediated syncope disclosed by the polymorphic sites of the adrenergic receptor gene alpha2B-AR. PLoS ONE 2015, 10, e0120788. [Google Scholar] [CrossRef]
  15. Hernandez-Pacheco, G.; Gonzalez-Hermosillo, A.; Murata, C.; Yescas, P.; Espinola-Zavaleta, N.; Martinez, M.; Serrano, H. Arg347Cys polymorphism of alpha1a-adrenergic receptor in vasovagal syncope. Case-control study in a Mexican population. Auton. Neurosci. Basic Clin. 2014, 183, 66–71. [Google Scholar] [CrossRef]
  16. Lelonek, M.; Pietrucha, T.; Matyjaszczyk, M.; Goch, J.H. Polymorphism C1114G of gene encoding the cardiac regulator of G-protein signaling 2 may be associated with number of episodes of neurally mediated syncope. Arch. Med. Res. 2009, 40, 191–195. [Google Scholar] [CrossRef]
  17. Mitro, P.; Habalova, V.; Evin, L.; Muller, E.; Simurda, M.; Slaba, E.; Murin, P.; Valocik, G. Gene Polymorphism of the Adenosine A2a Receptor in Patients with Vasovagal Syncope. Pacing Clin. Electrophysiol. PACE 2016, 39, 330–337. [Google Scholar] [CrossRef]
  18. Saadjian, A.Y.; Gerolami, V.; Giorgi, R.; Mercier, L.; Berge-Lefranc, J.L.; Paganelli, F.; Ibrahim, Z.; By, Y.; Gueant, J.L.; Levy, S.; et al. Head-up tilt induced syncope and adenosine A2A receptor gene polymorphism. Eur. Heart J. 2009, 30, 1510–1515. [Google Scholar] [CrossRef]
  19. Olde Nordkamp, L.R.; Wieling, W.; Zwinderman, A.H.; Wilde, A.A.; van Dijk, N. Genetic aspects of vasovagal syncope: A systematic review of current evidence. Europace. 2009, 11, 414–420. [Google Scholar] [CrossRef]
  20. Sorrentino, S.; Forleo, C.; Iacoviello, M.; Guida, P.; D’Andria, V.; Favale, S. Lack of association between genetic polymorphisms affecting sympathetic activity and tilt-induced vasovagal syncope. Auton. Neurosci. Basic Clin. 2010, 155, 98–103. [Google Scholar] [CrossRef]
  21. Ungar, A.; Del Rosso, A.; Giada, F.; Bartoletti, A.; Furlan, R.; Quartieri, F.; Lagi, A.; Morrione, A.; Mussi, C.; Lunati, M.; et al. Early and late outcome of treated patients referred for syncope to emergency department: The EGSYS 2 follow-up study. Eur. Heart J. 2010, 31, 2021–2026. [Google Scholar] [CrossRef] [PubMed]
  22. Arnar, D.O. Syncope in patients with structural heart disease. J. Intern. Med. 2013, 273, 336–344. [Google Scholar] [CrossRef] [PubMed]
  23. Klein, K.M.; Berkovic, S.F. Genetics of vasovagal syncope. Auton. Neurosci. Basic Clin. 2014, 184, 60–65. [Google Scholar] [CrossRef]
  24. Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. Off. J. Am. Coll. Med. Genet. 2015, 17, 405–424. [Google Scholar] [CrossRef]
  25. Kelly, M.A.; Caleshu, C.; Morales, A.; Buchan, J.; Wolf, Z.; Harrison, S.M.; Cook, S.; Dillon, M.W.; Garcia, J.; Haverfield, E.; et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: Recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel. Genet. Med. Off. J. Am. Coll. Med. Genet. 2018, 20, 351–359. [Google Scholar] [CrossRef] [PubMed]
  26. Fitzpatrick, A.P.; Theodorakis, G.; Vardas, P.; Sutton, R. Methodology of head-up tilt testing in patients with unexplained syncope. J. Am. Coll. Cardiol. 1991, 17, 125–130. [Google Scholar] [CrossRef]
  27. Herman, D.S.; Lam, L.; Taylor, M.R.; Wang, L.; Teekakirikul, P.; Christodoulou, D.; Conner, L.; DePalma, S.R.; McDonough, B.; Sparks, E.; et al. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 2012, 366, 619–628. [Google Scholar] [CrossRef]
  28. Woo, A.; Rakowski, H.; Liew, J.C.; Zhao, M.S.; Liew, C.C.; Parker, T.G.; Zeller, M.; Wigle, E.D.; Sole, M.J. Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: Critical functional sites determine prognosis. Heart (Br. Card. Soc.) 2003, 89, 1179–1185. [Google Scholar] [CrossRef]
  29. Marquez, M.F.; Hernandez-Pacheco, G.; Hermosillo, A.G.; Gomez, J.R.; Cardenas, M.; Vargas-Alarcon, G. The Arg389Gly beta1-adrenergic receptor gene polymorphism and susceptibility to faint during head-up tilt test. Europace 2007, 9, 585–588. [Google Scholar] [CrossRef]
  30. Lelonek, M.; Pietrucha, T.; Matyjaszczyk, M.; Goch, J.H. Mutation T/C,Ile 131 of the gene encoding the alfa subunit of the human Gs protein and predisposition to vasovagal syncope. Circ. J. Off. J. Jpn. Circ. Soc. 2008, 72, 558–562. [Google Scholar] [CrossRef]
  31. Lelonek, M.; Pietrucha, T.; Matyjaszczyk, M.; Goch, J.H. A novel approach to syncopal patients: Association analysis of polymorphisms in G-protein genes and tilt outcome. Europace 2009, 11, 89–93. [Google Scholar] [CrossRef] [PubMed]
  32. Ioannidis, J.P.; Boffetta, P.; Little, J.; O’Brien, T.R.; Uitterlinden, A.G.; Vineis, P.; Balding, D.J.; Chokkalingam, A.; Dolan, S.M.; Flanders, W.D.; et al. Assessment of cumulative evidence on genetic associations: Interim guidelines. Int. J. Epidemiol. 2008, 37, 120–132. [Google Scholar] [CrossRef] [PubMed]
  33. Menon, S.C.; Michels, V.V.; Pellikka, P.A.; Ballew, J.D.; Karst, M.L.; Herron, K.J.; Nelson, S.M.; Rodeheffer, R.J.; Olson, T.M. Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. Clin. Genet. 2008, 74, 445–454. [Google Scholar] [CrossRef] [PubMed]
  34. Geisterfer-Lowrance, A.A.; Kass, S.; Tanigawa, G.; Vosberg, H.P.; McKenna, W.; Seidman, C.E.; Seidman, J.G. A molecular basis for familial hypertrophic cardiomyopathy: A beta cardiac myosin heavy chain gene missense mutation. Cell 1990, 62, 999–1006. [Google Scholar] [CrossRef]
  35. Maron, B.J.; Maron, M.S.; Semsarian, C. Genetics of hypertrophic cardiomyopathy after 20 years: Clinical perspectives. J. Am. Coll. Cardiol. 2012, 60, 705–715. [Google Scholar] [CrossRef]
  36. Maron, B.J.; Seidman, J.G.; Seidman, C.E. Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 2004, 44, 2125–2132. [Google Scholar] [CrossRef]
  37. Olivotto, I.; Maron, M.S.; Autore, C.; Lesser, J.R.; Rega, L.; Casolo, G.; De Santis, M.; Quarta, G.; Nistri, S.; Cecchi, F.; et al. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 2008, 52, 559–566. [Google Scholar] [CrossRef]
Table
Table 1. List of cardiac syncope-related genes.
Table 1. List of cardiac syncope-related genes.
Disease-Related GenesGenes
Channelopathy genes (n = 43)KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1, KCNJ5, CALM1, CALM2, CALM3, CACNB2, CACNA2D1, GPD1L, SCN1B, KCNE3, SCN3B, HCN4, KCND3, ABCC9, FGF12, KCND2, KCNE5, KCNJ8, RANGRF, SCN10A, SEMA3A, SLMAP, TRPM4, RYR2, CASQ2, TRDN, PRKAG2, NPPA, KCNA5, GJA5, NUP155, CDH2
Cardiomyopathy genes (n = 50)PKP2, TGFB3, TMEM43, DSP, DSG2, DSC2, JUP, CTNNA3, DES, LMNA, PLN, TTN, TECRL, CALR3, ACTN2, LDB3, MYPN, FLNC, MYH7, MYLK2, MYL2, ACTC1, CSRP3, TNNC1, MYH6, VCL, MYOZ2, JPH2, TNNT2, NEXN, TPM1, MYBPC3, TNNI3, MYL3, PRDM16, PSEN2, RAF1, SGCD, LAMA4, EYA4, GATAD1, FKTN, RBM20, BAG3, CRYAB, PSEN1, DMD, ANKRD1, TMPO, TAZ
Primary pulmonary hypertension genes (n = 5)BMPR2, SMAD9, CAV1, KCNK3, ACVRL1
Table
Table 2. Baseline characteristics of the study population.
Table 2. Baseline characteristics of the study population.
CharacteristicValue (n = 54)
Age (years)41.3 ± 8.9
Female (%)36 (66.7)
Body weight (kg)60.0 ± 10.9
Height (cm)164.1 ± 7.7
Body mass index (kg/m2)22.1 ± 3.0
Family history of syncope17 (31.5)
Mother13 (24.1)
Father0
Brother0
Sister4 (7.4)
Aunt2 (3.7)
Son1 (1.9)
Number of syncopal episodes6 (5–10)
Number of pre-syncopal episodes2 (0–20)
Duration of syncope (years)12.5 (8–22.2)
Diagnostic test
12 lead electrocardiogram
Normal sinus rhythm50 (92.6%)
Sinus bradycardia4 (7.4%)
Echocardiogram
Ejection fraction (%)61.8 ± 4.6
Head up tilt test
Negative1 (1.9)
Positive53 (98.2)
Vasodepressor35 (64.8)
Cardio-inhibition7 (13.0)
Mixed11 (20.4)
Syncope-related injury30 (55.6)
Major injury (tooth fracture)2 (3.7)
Minor injury31 (57.4)
Contusion17 (31.5)
Laceration12 (22.2)
Seizure-like activity6 (11.1)
Data are presented as mean ± standard deviation, number (%) or median (range).
Table
Table 3. Genetic and clinical information of patients with recurrent syncope carrying likely pathogenic variants.
Table 3. Genetic and clinical information of patients with recurrent syncope carrying likely pathogenic variants.
Patient
ID		GeneNucleotide ChangeProtein ChangeZyggnomAD East AsianKRGDBPolyphen-2SIFTACMG Classification * (Evidences)Number of Syncopal EpisodesFamily History of Syncope
PT-001TTNc.27755_27756insTCTTCTTTGTATGp.Thr9253Leufs*23HetN/AN/AN/AN/ALPV
(PVS1, and PM2)		10Mother and sister
PT-104MYH7c.2608C>Tp.(Arg870Cys)Het0.00010.0005Probably damagingDeleteriousPV
(PS4, PM1, PM2, PM5, and PP3)		5Son
Abbreviations: gnomAD, Genome Aggregation Database; Het, heterozygous; KRGDB, Korean Reference Genome Database; LPV, likely pathogenic variant; N/A, not applicable. * Identified variants were classified according to the standards and guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [24].
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lee, S.H.; Park, J.E.; Ki, C.-S.; Park, S.-J.; On, Y.K.; Park, K.-M.; Kim, J.S. Genetic Analysis of Cardiac Syncope-Related Genes in Korean Patients with Recurrent Neurally Mediated Syncope. J. Cardiovasc. Dev. Dis. 2022, 9, 265. https://doi.org/10.3390/jcdd9080265

AMA Style

Lee SH, Park JE, Ki C-S, Park S-J, On YK, Park K-M, Kim JS. Genetic Analysis of Cardiac Syncope-Related Genes in Korean Patients with Recurrent Neurally Mediated Syncope. Journal of Cardiovascular Development and Disease. 2022; 9(8):265. https://doi.org/10.3390/jcdd9080265

Chicago/Turabian Style

Lee, Sung Ho, Jong Eun Park, Chang-Seok Ki, Seung-Jung Park, Young Keun On, Kyoung-Min Park, and June Soo Kim. 2022. "Genetic Analysis of Cardiac Syncope-Related Genes in Korean Patients with Recurrent Neurally Mediated Syncope" Journal of Cardiovascular Development and Disease 9, no. 8: 265. https://doi.org/10.3390/jcdd9080265

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop