Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Forensic Science, Medicine and Pathology
Published in: Forensic Science, Medicine and Pathology 3/2018

01-09-2018 | Original Article

Feasibility of analysis of the SCN5A gene in paraffin embedded samples in sudden infant death cases at the Pretoria Medico-Legal Laboratory, South Africa

Authors: Barbara Ströh van Deventer, Lorraine du Toit-Prinsloo, Chantal van Niekerk

Published in: Forensic Science, Medicine and Pathology | Issue 3/2018

Login to get access

Abstract

To determine variations in the SCN5A gene linked to inherited cardiac arrhythmogenic disorders in sudden, unexplained infant death (SUID) cases examined at the Pretoria Medico-Legal Laboratory, South Africa. A retrospective study was conducted on SUID cases and controls, analyzing DNA extracted from archived formalin-fixed, paraffin-embedded (FFPE) myocardial tissue samples as well as blood samples. A total of 48 FFPE tissue samples (cases), 10 control FFPE tissue samples and nine control blood samples were included. DNA extracted from all samples was used to test for variations in the SCN5A gene by using high resolution melt (HRM) real-time PCR and sequencing. Genetic analysis showed 31 different single nucleotide variants in the entire study population (n = 67). Five previously reported variants of known pathogenic significance, and 14 variants of benign clinical significance, were identified. The study found 12 different variants in the cases that were not published in any database or literature and were considered novel. Of these novel variants, two were predicted as “probably damaging” with a high level of certainty (found in four case samples), one (identified in another case sample) was predicted to be “possibly damaging” with a 50% chance of being disease-causing, and nine were predicted to be benign. This study shows the significant added value of using genetic testing in determining the cause of death in South African SUID cases. Considering the high heritability of these arrhythmic disorders, post mortem genetic testing could play an important role in the understanding of the pathogenesis thereof and could also aid in the diagnosis and treatment of family members at risk, ultimately preventing similar future cases.
Literature
1.
Doolan A, Langlois N, Chiu C, et al. Postmortem molecular analysis of KCNQ1 and SCN5A genes in sudden unexplained death in young Australians. Int J Cardiol. 2008;127:138–41.CrossRefPubMed
2.
Carroll R, Wood JN. Sudden unexpected infant death: a compassionate forensic approach to care. Clin Pediatr Emerg Med. 2012;13:239–48.CrossRef
3.
Neubauer J, Lecca MR, Russo G, et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017;25:404–9.CrossRefPubMedPubMedCentral
4.
5.
Wang D, Shah KR, Yon Um S, et al. Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. Forensic Sci Int. 2014;237:90–9.CrossRefPubMed
6.
du Toit-Prinsloo L, Dempers J, Verster J, et al. Toward a standardized investigation protocol in sudden unexpected deaths in infancy in South Africa: a multicenter study of medico-legal investigation procedures and outcomes. Forensic Sci Med Pathol. 2013;9:344–50.CrossRefPubMed
7.
Opdal SH, Rognum TO. Gene variants predisposing to SIDS: current knowledge. Forensic Sci Med Pathol. 2011;7:26–36.CrossRefPubMed
8.
Moon RY. Task force on sudden infant death syndrome. SIDS and other sleep-related infant deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics. 2011;128:1030–9.CrossRefPubMed
9.
Krous HF, Beckwith JB, Byard RW, et al. Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. Pediatrics. 2004;114:234–8.CrossRefPubMed
10.
Byard RW. Changing infant death rates: diagnostic shift, success story, or both? Forensic Sci Med Pathol. 2013;9:1–2.CrossRefPubMed
11.
Pasquale-Styles MA, Tackitt PL, Schmidt CJ. Infant death scene investigation and the assessment of potential risk factors for asphyxia: a review of 209 sudden unexpected infant deaths. J Forensic Sci. 2007;52:924–9.CrossRefPubMed
12.
Dempers JJ, Coldrey J, Burger EH, et al. The institution of a standardized investigation protocol for sudden infant death in the Eastern Metropole, Cape Town, South Africa. J Forensic Sci. 2016;61:1508–14.CrossRefPubMedPubMedCentral
13.
14.
Byard RW. Possible mechanisms responsible for the sudden infant death syndrome. J Paediatr Child Health. 1991;27:147–57.CrossRefPubMed
15.
Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007;115:361–70.CrossRefPubMed
16.
Evans A, Bagnall RD, Duflou J, et al. Postmortem review and genetic analysis in sudden infant death syndrome: an 11-year review. Hum Pathol. 2013;44:1730–6.CrossRefPubMed
17.
Byard RW. Sudden pediatric death: issues and overview. In: Byard RW, editor. Sudden death in the young. 3rd ed. New York: Cambridge University Press; 2010. p. 1–2.CrossRef
18.
19.
Kibel MA, Molteno CD, de Decker R. Cot death controversies. SAMJ. 2005;95:853–7.PubMed
20.
Filiano JJ, Kinney HC. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. Biol Neonate. 1994;65:194–7.CrossRefPubMed
21.
22.
Garcia AJ, Koschnitzky JE, Ramirez J. The physiological determinants of sudden infant death syndrome. Respir Physiol Neurobiol. 2013;189:288–300.CrossRefPubMed
23.
24.
Stattin E, Westin IM, Cederquist K, et al. Genetic screening in sudden cardiac death in the young can save future lives. Int J Legal Med. 2016;130:59–66.CrossRefPubMed
25.
Crotti L, Kotta MC. The role of genetics in primary ventricular fibrillation, inherited channelopathies and cardiomyopathies. Int J Cardiol. 2017;237:45–8.CrossRefPubMed
26.
Abriel H, Zaklyazminskaya EV. Cardiac channelopathies: genetic and molecular mechanisms. Gene. 2013;517:1–11.CrossRefPubMed
27.
28.
29.
Semsarian C, Ingles J, Wilde AAM. Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives. Eur Heart J. 2015;36:1290–6.CrossRefPubMed
30.
Monteforte N, Napolitano C, Priori SG. Genetics and arrhythmias: diagnostic and prognostic applications. Rev Esp Cardiol. 2012;65:278–86.CrossRefPubMed
31.
Ackerman MJ, Marcou CA, Tester DJ. Personalized medicine: genetic diagnosis for inherited cardiomyopathies/channelopathies. Rev Esp Cardiol. 2013;66:298–307.CrossRefPubMed
32.
George AL. Inherited disorders of voltage-gated sodium channels. J Clin Investig. 2005;115:1990–9.CrossRefPubMed
33.
Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis. 2008;51:213–28.CrossRefPubMedPubMedCentral
34.
Wang S, Li L, Tao R, et al. Ion channelopathies associated genetic variants as the culprit for sudden unexplained death. Forensic Sci Int. 2017;275:128–37.CrossRefPubMed
35.
Millat G, Chevalier P, Restier-Milon L, et al. Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet. 2006;70:214–27.CrossRefPubMed
36.
37.
Takahata T, Yasui-Furukori N, Sasaki S, et al. Nucleotide changes in the translated region of SCN5A from Japanese patients with Brugada syndrome and control subjects. Life Sci. 2003;72:2391–9.CrossRefPubMed
38.
Daimi H, Khelil AH, Hamda KB, et al. Absence of family history and phenotype-genotype correlation in pediatric Brugada syndrome: more burden to bear in clinical and genetic diagnostics. Pediatr Cardiol. 2015;36:1090–6.CrossRefPubMed
39.
Kiehne N, Kauferstein S. Mutations in the SCN5A gene: evidence for a link between long QT syndrome and sudden death? Forensic Sci Int Genet. 2007;1:170–4.CrossRefPubMed
40.
Park HS, Kim YN, Lee YS, et al. Genetic analysis of SCN5A in Korean patients associated with atrioventricular conduction block. Genomic Inform. 2012;10:110–6.CrossRef
41.
Noseworthy PA, Newton-Cheh C. Genetic determinants of sudden cardiac death. Circulation. 2008;118:1854–63.CrossRefPubMed
42.
Splawski I, Timothy KW, Tateyama M, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science. 2002;297:1333–6.CrossRefPubMed
43.
Plant LD, Bowers PN, Liu Q, et al. A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. J Clin Investig. 2006;116:430–5.CrossRefPubMed
44.
45.
46.
Makita N, Seki A, Sumitomo N, et al. A connexin 40 mutation associated with a malignant variant of progressive familial heart block type-1. Circ Arrhythm Electrophysiol. 2012;5:163–72.CrossRefPubMedPubMedCentral
47.
Sayeed Z, Salam A, Haque Z, et al. Brugada syndrome with a novel missense mutation in SCN5A gene: a case report from Bangladesh. Indian Heart J. 2014;66:104–7.CrossRefPubMed
48.
Shim SH, Ito M, Maher T, et al. Gene sequencing in neonates and infants with the long QT syndrome. Genet Test. 2005;9:281–4.CrossRefPubMed
49.
Uzieblo-Zyczkowska B, Gielerak G, Siedlecki P, et al. Genetic diversity of SCN5A gene and its possible association with the concealed form of Brugada syndrome development in Polish group of patients. Bio Med Res Int. 2014;2014:462609.
50.
Hertz CL, Christiansen SL, Ferrero-Miliani L, et al. Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart. Int J Legal Med. 2016;130:91–102.CrossRefPubMed
51.
Veerman CC, Wilde AAM, Lodder EM. The cardiac sodium channel gene SCN5A and its gene product Nav1.5: role in physiology and pathophysiology. Gene. 2015;573:177–87.CrossRefPubMed
52.
53.
Otagiri T, Kijima K, Osawa M, et al. Cardiac ion channel gene mutations in sudden infant death syndrome. Pediatr Res. 2008;64:482–7.CrossRefPubMed
54.
Millat G, Kugener B, Chevalier P, et al. Contribution of long-QT syndrome genetic variants in sudden infant death syndrome. Pediatr Cardiol. 2009;30:502–9.CrossRefPubMed
55.
Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007;49:240–6.CrossRefPubMed
56.
Campuzano O, Sanchez-Molero O, Allegue C, et al. Post-mortem genetic analysis in juvenile cases of sudden cardiac death. Forensic Sci Int. 2014;245:30–7.CrossRefPubMed
57.
Clatot J, Ziyadeh-Isleem S, Maugenre S, et al. Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Nav1.5 α-subunits. Cardiovasc Res. 2012;96:53–63.CrossRefPubMedPubMedCentral
58.
Kubus P, Janousek J. Sudden cardiac death in children and young adults - epidemiology and prevention. Cor et Vasa. 2012;54:223–6.CrossRef
59.
Giudicessi JR, Ackerman MJ. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmic syndromes. Transl Res. 2013;161:1–14.CrossRefPubMed
60.
Mensah GA, Peprah EK, Sampson UKA, et al. H3 Africa comes of age. CVJ Africa. 2015;26:5–7.
Metadata
Title
Feasibility of analysis of the SCN5A gene in paraffin embedded samples in sudden infant death cases at the Pretoria Medico-Legal Laboratory, South Africa
Authors
Barbara Ströh van Deventer
Lorraine du Toit-Prinsloo
Chantal van Niekerk
Publication date
01-09-2018
Publisher
Springer US
Published in
Forensic Science, Medicine and Pathology / Issue 3/2018
Print ISSN: 1547-769X
Electronic ISSN: 1556-2891
DOI
https://doi.org/10.1007/s12024-018-9995-5

Other articles of this Issue 3/2018

Forensic Science, Medicine and Pathology 3/2018 Go to the issue

Case Report

Anesthetized by chloroform before hanging

Original Article

Point-of-care hemoglobin A1c testing in postmortem examination

Images in Forensics

“Defense” type wounds in suicide

Case Report

Neurofibromatosis 1 and massive hemothorax: a fatal combination

Original Article

Investigation into the potential for post-mortem formation of carboxyhemoglobin in bodies retrieved from fires

Original Article

Lymphoma in autopsy cases