Skip to main content
SpringerLink
Log in

Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study

  • Original Article
  • Published:
International Journal of Legal Medicine Aims and scope Submit manuscript

Abstract

Sudden infant death syndrome (SIDS) is a frequent cause of death among infants. The etiology of SIDS is unknown and several theories, including fatal ventricular arrhythmias, have been suggested. We performed an epidemiological and genetic investigation of SIDS victims to estimate the presence of inherited long QT syndrome (LQTS) as a contributor for SIDS. Forty-one consecutively collected and unrelated SIDS cases were characterized by clinical and epidemiological criteria. We performed a comprehensive gene mutation screening with single-strand conformation polymorphism analysis and sequencing techniques of the most relevant LQTS genes to assess mutation frequencies. In vitro characterization of identified mutants was subsequently performed by heterologous expression experiments in Chinese hamster ovary cells and in Xenopus laevis oocytes. A positive family history for LQTS was suspected by mild prolonged Q-T interval in family members in 2 of the 41 SIDS cases (5%). In neither case, a family history of sudden cardiac death was present nor a mutation could be identified after thorough investigation. In another SIDS case, a heterozygous missense mutation (H105L) was identified in the N-terminal region of the KCNQ1 (LQTS 1) gene. Despite absence of this mutation in the general population and a high conservational degree of the residue H105 during evolution, electrophysiological investigations failed to show a significant difference between wild-type and KCNQ1H105L/minK-mediated IKs currents. Our data suggest that a molecular diagnosis of SIDS related to LQTS genes is rare and that, even when an ion channel mutation is identified, this should be regarded with caution unless a pathophysiological relationship between SIDS and the electrophysiological characterization of the mutated ion channel has been demonstrated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Dwyer T, Ponsonby AL (1995) SIDS epidemiology and incidence. Pediatr Ann 24:354–356

    Google Scholar 

  2. Statistisches Bundesamt Deutschland, Statistischer Informationsservice, Gustav-Stresemann-Ring 11, 65189 Wiesbaden. Gestorbene Säuglinge nach Alter und ausgewählten Todesursachen (ICD10: R95)

  3. Fitzgerald K (2001) The “Reduce the risks” campaign, SIDS International, the Global Strategy Task Force and the European Society for Study and Prevention of Infant Death. In: Byard RW, Krous HF (eds) Sudden infant death syndrome. Problems, progress and possibilities. University Press, Oxford, pp 310–318

    Google Scholar 

  4. James TN (1968) Sudden death in babies: new observations in the heart. Am J Cardiol 22:457–506

    Article  PubMed  Google Scholar 

  5. Bajanowski T, Ortmann C, Teige K, Wedekind H, Zack F, Röse I, Brinkmann B (2003) Pathological changes of the heart in sudden infant death. Int J Leg Med 117:193–203

    Article  CAS  Google Scholar 

  6. Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, Stramba-Badiale M, Richard TA, Berti MR, Bloise R (2000) A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 343:262–267

    Article  PubMed  CAS  Google Scholar 

  7. Schwartz PJ, Priori SG, Bloise R, Napolitano C, Ronchetti E, Piccinini A, Goj C, Breithardt G, Schulze-Bahr E, Wedekind H, Naftoli J (2001) Molecular diagnosis in a child with sudden infant death syndrome. Lancet 358:1342–1343

    Article  PubMed  CAS  Google Scholar 

  8. Schwartz PJ (1976) Cardiac sympathetic innervation and the sudden infant death syndrome. Am J Med 60:167–172

    Article  PubMed  CAS  Google Scholar 

  9. Maron BJ, Clark CE, Goldstein RE, Epstein SE (1976) Potential role of Q-T interval prolongation in sudden infant death syndrome. Circulation 54:423–430

    PubMed  CAS  Google Scholar 

  10. Kukolich MK, Telsey A, Ott J, Motulsky AG (1977) Sudden infant death syndrome: normal Q-T interval in ECGs of relatives. Pediatrics 60:51–54

    PubMed  CAS  Google Scholar 

  11. Southall DP (1983) Identification of infants destined to die unexpectedly during infancy: evaluation of predictive importance of prolonged apnoea and disorders of cardiac rhythm or conduction. Br Med J 286:1092–1096

    Google Scholar 

  12. Southall DP, Arrowsmith WA, Stebbens V, Alexander JR (1986) QT interval measurements before sudden infant death syndrome. Arch Dis Child 61:327–333

    PubMed  CAS  Google Scholar 

  13. Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P, Bosi G, Giorgetti R, Grancini F, Marni ED, Perticone F, Rosti D, Salice P (1998) Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 338:1709–1714

    Article  PubMed  CAS  Google Scholar 

  14. Schwartz PJ, Montemerlo M, Facchini M, Salice P, Rosti D, Poggio G, Giorgetti R (1982) The QT interval throughout the first 6 months of life: a prospective study. Circulation 66:496–501

    PubMed  CAS  Google Scholar 

  15. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA (2001) Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 286:2264–2269

    Article  PubMed  CAS  Google Scholar 

  16. Ackerman MJ, Tester DJ, Bell CM, Towbin JA, January CT, Makielski JC, Sturner WQ (2002) Cardiac channel mutations in SIDS: a population-based molecular study in 93 SIDS victims. Circulation 106(suppl II):II–167

    Google Scholar 

  17. Christiansen M, Tonder N, Larsen LA, Andersen PS, Simonsen H, Oyen N, Kanters JK, Jacobsen JR, Fosdal I, Wettrell G, Kjeldsen K (2005) Mutations in the HERG K+-ion channel: a novel link between long QT syndrome and sudden infant death syndrome. Am J Cardiol 95:433–434

    Article  PubMed  CAS  Google Scholar 

  18. Brooks DR, Krous HF, Burton JL, McKinley J, McKinley W (1994) Results of a pilot test of the global strategy workshop's international standardized autopsy protocol (SAP) in Georgia. In: Sudden infant death syndrome (SIDS), 3rd SIDS International Conference, Stavanger, Norway 31.07.-04.08.1994 Program and abstracts, p 155

  19. Bajanowski T, Fürst P, Wilmers K, Beike J, Köhler H, Brinkmann B (2002) Dioxin in infants—an environmental hazard? Int J Leg Med 116:27–32

    Article  CAS  Google Scholar 

  20. Beckwith J (1970) Discussion of terminology and definition of the sudden infant death syndrome. University of Washington Press, Seattle

    Google Scholar 

  21. Willinger M, James LS, Catz C (1991) Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol 11:677–684

    Article  PubMed  CAS  Google Scholar 

  22. Taylor EM, Emery JL (1990) Categories of preventable unexpected infant deaths. Arch Dis Child 65:535–539

    Article  PubMed  CAS  Google Scholar 

  23. Loddenkötter B, Becker K, Hohoff C, Brinkmann B, Bajanowski T (2005) Real-time quantitative PCR assay for the detection of Helicobacter pylori: no association with sudden infant death syndrome. Int J Leg Med 119:202–206

    Article  Google Scholar 

  24. Walsh PS, Metzger DA, Higuchi R (1991) Chelex-100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. BioTechniques 10:506–513

    PubMed  CAS  Google Scholar 

  25. Higuchi R (1989) Simple and rapid preparation of samples for PCR. In: Ehrlich HA (ed) PCR-technology: principles and applications for DNA amplification, Chapter 4. Stockton Press, New York, pp 31–38

    Google Scholar 

  26. Chou Q, Russell M, Birch DE, Raymond J, Bloch W (1992) Prevention of pre-PCR mis-priming and primer dimerization improves low-copy-number amplifications. Nucleic Acids Res 20:1717–1723

    Article  PubMed  CAS  Google Scholar 

  27. Don RH, Cox PT, Wainwright BJ, Baker K, Mattick JS (1991) “Touchdown” PCR to circumvent spurious priming during gene amplification. Nucleic Acids Res 19:4008

    Article  PubMed  CAS  Google Scholar 

  28. Wang Q, Zhizhong L, Jiaxiang S, Keating MT (1996) Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics 34:9–16

    Article  PubMed  CAS  Google Scholar 

  29. Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT (1998) Genomic structure of three long QT syndrome genes: KCNQ1, HERG, and KCNE1. Genomics 51:86–97

    Article  PubMed  CAS  Google Scholar 

  30. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SAN (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 3:175–187

    Article  Google Scholar 

  31. Findeisen M, Vennemann M, Brinkmann B, Ortmann C, Röse I, Köpcke W, Jorch G, Bajanowski T, and the GeSID Group (2004) German study on sudden infant death (GeSID): design, epidemiological and pathological profile. Int J Leg Med 118:163–169

    Article  CAS  Google Scholar 

  32. Moss AJ, Schwartz PJ (1982) Delayed repolarization (QT or QTU prolongation) and malignant ventricular arrhythmias. Mod Concepts Cardiovasc Dis 51:85–90

    PubMed  CAS  Google Scholar 

  33. Paulussen AD, Gilissen RA, Armstrong M, Doevendans PA, Verhasselt P, Smeets HJ, Schulze-Bahr E, Haverkamp W, Breithardt G, Cohen N, Aerssens J (2004) Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med 82:182–188

    Article  PubMed  CAS  Google Scholar 

  34. Kääb S, Schulze-Bahr E (2005) Susceptibility genes and modifiers for cardiac arrhythmias. Cardiovasc Res (in press)

  35. Chevalier P, Rodriguez C, Bontemps L, Miquel M, Kirkorian G, Rousson R, Potet F, Schott JJ, Baro I, Touboul P (2001) Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc Res 50:386–398

    Article  PubMed  CAS  Google Scholar 

  36. Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL Jr, Goldstein SA (2000) A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A 97:10613–10618

    Article  PubMed  CAS  Google Scholar 

  37. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM (2002) Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 105:1943–1948

    Article  PubMed  CAS  Google Scholar 

  38. Eskdale J, Keijsers V, Huizinga T, Gallagher G (1999) Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun 1:151–155

    Article  PubMed  CAS  Google Scholar 

  39. Narita N, Narita M, Takashima S, Nakayama M, Nagai T, Okado N (2001) Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population. Pediatrics 107:690–692

    Article  PubMed  CAS  Google Scholar 

  40. Priori SG, Napolitano C, Giordano U, Collisani G, Memmi M (2000) Brugada syndrome and sudden cardiac death in children. Lancet 355:808–809

    Article  PubMed  CAS  Google Scholar 

  41. Romano C, Gemme G, Pongiglione R (1963) Aritmie cardiace rare delleta pedriatica: accessi per fibrillazione ventricolare parossistica. Clin Pediatr 45:656–683

    CAS  Google Scholar 

  42. Ward OC (1964) A new familial cardiac syndrome in children. J Ir Med Assoc 54:103–109

    PubMed  CAS  Google Scholar 

  43. Wedekind H, Smits JP, Schulze-Bahr E, Arnold R, Veldkamp MW, Bajanowski T, Borggrefe M, Brinkmann B, Warnecke I, Funke H, Bhuiyan ZA, Wilde AA, Breithardt G, Haverkamp W (2001) De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation 104:1158–1164

    Article  PubMed  CAS  Google Scholar 

  44. Schulze-Bahr E, Fenge H, Etzrodt D, Haverkamp W, Mönnig G, Wedekind H, Breithardt G, Kehl HG (2004) Long QT syndrome and life threatening arrhythmia in a newborn: molecular diagnosis and treatment response. Heart 90:13–16

    Article  PubMed  CAS  Google Scholar 

  45. Iwasa H, Kurabayashi M, Nagai R, Nakamura Y, Tanaka T (2001) Multiple single-nucleotide polymorphisms (SNPs) in the Japanese population in six candidate genes for long QT syndrome. J Hum Genet 46:158–162

    Article  PubMed  CAS  Google Scholar 

  46. Tesson F, Donger C, Denjoy I, Berthet M, Bennaceur M, Petit C, Coumel P, Schwarts K, Guicheney P (1996) Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange–Nielsen syndrome. J Mol Cell Cardiol 28:2051–2055

    Article  PubMed  CAS  Google Scholar 

  47. Larsen LA, Christiansen M, Vuust J, Andersen PS (1999) High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants. Human Mutat 13:318–327

    Article  CAS  Google Scholar 

  48. Akimoto K, Furutani M, Imamura S, Furutani Y, Kasanuki H, Takao A, Momma K, Matsuoka R (1998) Novel missense mutation (G601S) of HERG in a Japanese long QT syndrome family. Human Mutat Suppl 1:S184–S186

    Google Scholar 

  49. Lee MP, Hu RJ, Johnson LA, Feinberg AP (1997) Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith–Wiedemann syndrome chromosomal rearrangements. Nat Genet 15:181–185

    Article  PubMed  Google Scholar 

  50. Lai LP, Deng CL, Moss AJ, Kass RS, Liang C (1994) Polymorphism of the gene encoding a human minimal potassium ion channel (minK). Gene 151:339–340

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Marianne Schürenkamp, Susana Pereira, Marielies Hesse, Simone Helms, Bianca Foppe and Andrea Zeisser for excellent technical assistance. We thank Joachim Mueller for his critical revision of the manuscript.

This work was supported by grants from the IMF Funds (Innovative Medizinische Forschung, We-1-2-II/97-17); University of Münster, Germany; the Dr. Adolf Schilling Foundation, Münster, Germany; the Deutsche Forschungsgemeinschaft (SFB 556-A1, Schu1082/3-1 and FR 1625/1-1), Bonn, Germany; the Fondation Leducq, Paris, France; and the Federal Ministry of Education and Research, Germany, (BMBF 01 ED 9401; German study on sudden infant death, GeSID).

Author information

Authors and Affiliations

  1. Department of Cardiology and Angiology, University of Münster, Münster, Germany

    Horst Wedekind, Günter Breithardt, Thomas Wülfing, Gerold Mönnig, Wilhelm Haverkamp & Eric Schulze-Bahr

  2. Institute for Arteriosclerosis Research at the University of Münster, Münster, Germany

    Horst Wedekind, Günter Breithardt, Gerold Mönnig, Wilhelm Haverkamp & Eric Schulze-Bahr

  3. Institute of Legal Medicine, University of Essen, Essen, Germany

    Thomas Bajanowski

  4. Department of Anaesthesiology, University Hospital Hamburg, Hamburg, Germany

    Patrick Friederich & Cornelia Siebrands

  5. Center for Molecular Neurobiology Hamburg, (ZMNH), Hamburg, Germany

    Cornelia Siebrands & Birgit Engeland

  6. Institute of Legal Medicine, University of Münster, Münster, Germany

    Bernd Brinkmann

  7. Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster, Albert Schweitzer Str. 33, 48149, Münster, Germany

    Horst Wedekind

Authors
  1. Horst Wedekind
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Bajanowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick Friederich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Günter Breithardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Wülfing
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cornelia Siebrands
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Birgit Engeland
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gerold Mönnig
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wilhelm Haverkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bernd Brinkmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eric Schulze-Bahr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Horst Wedekind.

Additional information

H. Wedekind, T. Bajanowski and P. Friederich contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wedekind, H., Bajanowski, T., Friederich, P. et al. Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study. Int J Legal Med 120, 129–137 (2006). https://doi.org/10.1007/s00414-005-0019-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00414-005-0019-0

Keywords

Search

Navigation