Molecular Genetics of Sudden Infant Death Syndrome

Cornelius Courts, University of Bonn, Bonn, Germany

Published online: April 2013

DOI: 10.1002/9780470015902.a0022424

The sudden infant death syndrome (SIDS) is currently defined as the sudden unexpected death of an infant less than 1 year of age with onset of the fatal episode apparently occurring during sleep, which remains unexplained after a thorough investigation. SIDS, whose aetiology remains rather vague, is still the major cause of death among infants between 1 month and 1 year of age in industrialised countries with varying incidences in different subpopulations.

After touching on definitory approaches and several current hypotheses concerning SIDS aetiology, the triple risk hypothesis as an explanatory model for SIDS is introduced, followed by the discussion of associated genetic risk factors potentially contributing to or predisposing for the generation of a vulnerable infant that, when encountering an environmental trigger, may succumb to SIDS. An overview of current animal models for SIDS is presented and future prospects are briefly discussed.

Key Concepts:

  • A proper definition and strict adherence to diagnostic criteria is critical to valid SIDS research.
  • SIDS is multifactorial disease probably with a genetic predisposition.
  • The triple risk areas model is an explanatory approach that may be fitted to most hypotheses concerning SIDS aetiology.
  • Numerous and very different genetic variants are potentially predisposing for SIDS.
  • Current animal models for SIDS may be useful but can each only represent a subgroup of SIDS.
  • Functional studies of SIDS pathomechanisms are required.

Keywords: sudden infant death syndrome; triple risk model; genetic predisposition; brainstem hypothesis; SIDS animal model

Figure 1. (a) ‘Three risk areas model’ SIDS may occur, when at least but not limited to one factor from each area (Genetic, Individual and Environment) is present in the same infant. (b) TRAM: three risk areas model as an explicatory funnel. The pathomechanisms postulated in the various hypotheses (H1 to Hn) each account for a subgroup of SIDS cases. The ‘three risk areas model’ also allows for a combination of the effects of different and/or combined hypotheses (Hn+Hm), for example, immunologic and central nervous system hypotheses.
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 References
    Audero E, Coppi E, Mlinar B et al. (2008) Sporadic autonomic dysregulation and death associated with excessive serotonin autoinhibition. Science 321(5885): 130–133.
    book Beckwith JB (1970) "Discussion of the terminology and definition of the sudden infant death syndrome". In: Proceedings of the Second International Conference on Causes of Sudden Death in Infants. Seattle: University of Washington Press.
    Bettelheim KA, Luke RK, Johnston N, Pearce JL and Goldwater PN (2012) A possible murine model for investigation of pathogenesis of sudden infant death syndrome. Current Microbiology 64(3): 276–282.
    Byard RW and Lee V (2012) A re-audit of the use of definitions of sudden infant death syndrome (SIDS) in peer-reviewed literature. Journal of Forensic and Legal Medicine 19(8): 455–456.
    Courts C and Madea B (2011a) No association of IL-10 promoter SNP -592 and -1082 and SIDS. Forensic Science International 204(1–3): 179–181.
    Courts C and Madea B (2011b) Significant association of TH01 allele 9.3 and SIDS. Journal of Forensic Sciences 56(2): 415–417.
    Cummings KJ, Commons KG, Hewitt JC et al. (2011) Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS. Journal of Applied Physiology 111(3): 825–833.
    Dashash M, Pravica V, Hutchinson IV, Barson AJ and Drucker DB (2006) Association of sudden infant death syndrome with VEGF and IL-6 gene polymorphisms. Human Immunology 67(8): 627–633.
    Deixler E (2009) Sudden infant death syndrome (SIDS) caused by ATP-depletion following hyperventilation, tissue-hypoxia and hypermetabolism – a hypothesis. Zeitschrift fur Geburtshilfe und Neonatologie 213(4): 122–134.
    Denney RM, Koch H and Craig IW (1999) Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat. Human Genetics 105(6): 542–551.
    Erickson JT, Shafer G, Rossetti MD, Wilson CG and Deneris ES (2007) Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges. Respiratory Physiology & Neurobiology 159(1): 85–101.
    Erickson JT and Sposato BC (2009) Autoresuscitation responses to hypoxia-induced apnea are delayed in newborn 5-HT-deficient Pet-1 homozygous mice. Journal of Applied Physiology 106(6): 1785–1792.
    Ferrante L, Opdal SH, Vege A and Rognum TO (2008) TNF-alpha promoter polymorphisms in sudden infant death. Human Immunology 69(6): 368–373.
    Filonzi L, Magnani C, Lavezzi AM et al. (2009) Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis. Neurogenetics 10(1): 65–72.
    Filonzi L, Magnani C and Nonnis-Marzano F (2011) Confirmed association between monoamine oxidase A molecular polymorphisms and Sudden Infant Death Syndrome. Neurogenetics 12(1): 91–92.
    Haas C, Braun J, Bar W and Bartsch C (2009) No association of serotonin transporter gene variation with sudden infant death syndrome (SIDS) in Caucasians. Legal Medicine 11(suppl. 1): S210–S212.
    Hodges MR, Tattersall GJ, Harris MB et al. (2008) Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. Journal of Neuroscience 28(10): 2495–2505.
    Hofmann S, Jaksch M, Bezold R et al. (1997) Population genetics and disease susceptibility: characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease. Human Molecular Genetics 6(11): 1835–1846.
    Jensen LL, Rohde MC, Banner J and Byard RW (2012) Reclassification of SIDS cases – a need for adjustment of the San Diego classification? International Journal of Legal Medicine 126(2): 271–277.
    Keller E, Andreas A, Teifel-Greding J et al. (1990) DNA analysis of HLA class II and III genes in sudden infant death (SIDS). Beitrage zur Gerichtlichen Medizin 48: 285–290.
    Klintschar M and Heimbold C (2010) Questionable association between a monoamine oxidase A promoter polymorphism and sudden infant death syndrome. Neurogenetics 11(3): 367–368.
    Klintschar M and Heimbold C (2012) Association between a functional polymorphism in the MAOA gene and sudden infant death syndrome. Pediatrics 129(3): e756–e761.
    Klintschar M, Reichenpfader B and Saternus KS (2008) A functional polymorphism in the tyrosine hydroxylase gene indicates a role of noradrenalinergic signaling in sudden infant death syndrome. Journal of Pediatrics 153(2): 190–193.
    Korachi M, Pravica V, Barson AJ, Hutchinson IV and Drucker DB (2004) Interleukin 10 genotype as a risk factor for sudden infant death syndrome: determination of IL-10 genotype from wax-embedded postmortem samples. FEMS Immunology and Medical Microbiology 42(1): 125–129.
    Krous HF, Beckwith JB, Byard RW et al. (2004) Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. Pediatrics 114(1): 234–238.
    Lavezzi AM, Casale V, Oneda R, Weese-Mayer DE and Matturri L (2009) Sudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphe nuclei and serotonin transporter gene promoter polymorphism. Pediatric Research 66(1): 22–27.
    Li A and Nattie E (2008) Serotonin transporter knockout mice have a reduced ventilatory response to hypercapnia (predominantly in males) but not to hypoxia. Journal of Physiology 586(9): 2321–2329.
    Maher BS, Marazita ML, Rand C et al. (2006) 3′ UTR polymorphism of the serotonin transporter gene and sudden infant death syndrome: haplotype analysis. American Journal of Medical Genetics Part A 140(13): 1453–1457.
    Moscovis SM, Gordon AE, Al Madani OM et al. (2004) Interleukin-10 and sudden infant death syndrome. FEMS Immunology and Medical Microbiology 42(1): 130–138.
    Moscovis SM, Gordon AE, Al Madani OM et al. (2006) IL6 G-174C associated with sudden infant death syndrome in a Caucasian Australian cohort. Human Immunology 67(10): 819–825.
    Narita N, Narita M, Takashima S et al. (2001) Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population. Pediatrics 107(4): 690–692.
    Neary MT, Mohun TJ and Breckenridge RA (2012) Hypoxia, Long QT interval and Sudden Infant Death Syndrome (SIDS). Disease Models & Mechanisms. doi: 10.1242/dmm.010587.
    Nonnis-Marzano F, Maldini M, Filonzi L et al. (2008) Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome. Genomics 91(6): 485–491.
    Opdal SH, Opstad A, Vege A and Rognum TO (2003) IL-10 gene polymorphisms are associated with infectious cause of sudden infant death. Human Immunology 64(12): 1183–1189.
    Opdal SH and Rognum TO (2007) The IL6 -174G/C polymorphism and sudden infant death syndrome. Human Immunology 68(6): 541–543.
    Opdal SH, Rognum TO, Torgersen H and Vege A (1999a) Mitochondrial DNA point mutations detected in four cases of sudden infant death syndrome. Acta Paediatrica 88(9): 957–960.
    Opdal SH, Rognum TO, Vege A et al. (1998) Increased number of substitutions in the D-loop of mitochondrial DNA in the sudden infant death syndrome. Acta Paediatrica 87(10): 1039–1044.
    Opdal SH, Vege A, Egeland T, Musse MA and Rognum TO (2002) Possible role of mtDNA mutations in sudden infant death. Pediatric Neurology 27(1): 23–29.
    Opdal SH, Vege A and Rognum TO (2008) Serotonin transporter gene variation in sudden infant death syndrome. Acta Paediatrica 97(7): 861–865.
    Opdal SH, Vege A, Saugstad OD and Rognum TO (1994) Is partial deletion of the complement C4 genes associated with sudden infant death? European Journal of Pediatrics 153(4): 287–290.
    Opdal SH, Vege A, Stave AK and Rognum TO (1999b) The complement component C4 in sudden infant death. European Journal of Pediatrics 158(3): 210–212.
    Panigrahy A, Filiano J, Sleeper LA et al. (2000) Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome. Journal of Neuropathology and Experimental Neurology 59(5): 377–384.
    Paterson DS, Rivera KD, Broadbelt KG et al. (2010) Lack of association of the serotonin transporter polymorphism with the sudden infant death syndrome in the San Diego Dataset. Pediatric Research 68(5): 409–413.
    Pavone LM, Spina A, Rea S et al. (2009) Serotonin transporter gene deficiency is associated with sudden death of newborn mice through activation of TGF-beta1 signalling. Journal of Molecular and Cellular Cardiology 47(5): 691–697.
    Penatti E, Barina A, Schram K, Li A and Nattie E (2011) Serotonin transporter null male mouse pups have lower ventilation in air and 5% CO2 at postnatal ages P15 and P25. Respiratory Physiology & Neurobiology 177(1): 61–65.
    Perskvist N, Skoglund K, Edston E et al. (2008) TNF-alpha and IL-10 gene polymorphisms versus cardioimmunological responses in sudden infant death. Fetal and Pediatric Pathology 27(3): 149–165.
    Sabol SZ, Hu S and Hamer D (1998) A functional polymorphism in the monoamine oxidase A gene promoter. Human Genetics 103(3): 273–279.
    Schneider PM, Wendler C, Riepert T et al. (1989) Possible association of sudden infant death with partial complement C4 deficiency revealed by post-mortem DNA typing of HLA class II and III genes. European Journal of Pediatrics 149(3): 170–174.
    Summers AM, Summers CW, Drucker DB et al. (2000) Association of IL-10 genotype with sudden infant death syndrome. Human Immunology 61(12): 1270–1273.
    Vege A, Rognum TO, Scott H, Aasen AO and Saugstad OD (1995) SIDS cases have increased levels of interleukin-6 in cerebrospinal fluid. Acta Paediatrica 84(2): 193–196.
    Wallace DC (1994) Mitochondrial DNA sequence variation in human evolution and disease. Proceedings of the National Academy of Sciences of the USA 91(19): 8739–8746.
    Weese-Mayer DE, Berry-Kravis EM, Maher BS et al. (2003a) Sudden infant death syndrome: association with a promoter polymorphism of the serotonin transporter gene. American Journal of Medical Genetics Part A 117A(3): 268–274.
    Weese-Mayer DE, Zhou L, Berry-Kravis EM et al. (2003b) Association of the serotonin transporter gene with sudden infant death syndrome: a haplotype analysis. American Journal of Medical Genetics Part A 122A(3): 238–245.
 Further Reading
    book Byard RW (2011) Sudden infant death syndrome. In: Sudden Death in the Young, 3rd edn, pp. 555–630. Cambridge: Cambridge University Press.
    Courts C and Madea B (2010) Genetics of the sudden infant death syndrome. Forensic Science International 203(1–3): 25–33.
    Filiano JJ and Kinney HC (1994) A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. Biology of the Neonate 65(3–4): 194–197.
    Goldwater PN (2011) A perspective on SIDS pathogenesis. The hypotheses: plausibility and evidence. BMC Medicine 9: 64.
    book Hauck FR (2001) "Changing epidemiology". In: Sudden Infant Death Syndrome: Problems, Progress and Possibilities, pp. 31–57. London: Arnold.
    Hauck FR and Tanabe KO (2008) International trends in sudden infant death syndrome: stabilization of rates requires further action. Pediatrics 122(3): 660–666.
    Kinney HC and Thach BT (2009) The sudden infant death syndrome. New England Journal of Medicine 361(8): 795–805.
    Leach CE, Blair PS, Fleming PJ et al. (1999) Epidemiology of SIDS and explained sudden infant deaths. CESDI SUDI Research Group. Pediatrics 104(4): e43.
    Opdal SH and Rognum TO (2011) Gene variants predisposing to SIDS: current knowledge. Forensic Science, Medicine and Pathology 7(1): 26–36.
    Weese-Mayer DE, Ackerman MJ, Marazita ML and Berry-Kravis EM (2007) Sudden Infant Death Syndrome: review of implicated genetic factors. American Journal of Medical Genetics Part A 143A(8): 771–788.

Related Sub-Topics:

Molecular Genetics of Common and Complex Disease | Model Organisms and Human Disease | Mitochondrial Diseases | Evolution of Coding and Functional Modules
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Article Title: Molecular Genetics of Sudden Infant Death Syndrome
 
How to Cite close
Courts, Cornelius(Apr 2013) Molecular Genetics of Sudden Infant Death Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022424]