Genetic Factors Underlying Sudden Infant Death Syndrome

Figures & data

Table 1 Summary of Genetic Evidence by Disease Category

Disease Category	Summary of Evidence	Relevant Literature
Metabolic	Metabolic conditions with a genetic basis have been identified in SIDS cases. Many of these conditions are screened for in newborn screening programs, although there are case reports of infants who escaped diagnosis during life and went on to die suddenly in infancy.	Emery JL et al Lancet. 1988; 2(8601):29–31.^Citation23 Neubauer J et al Eur J Hum Genet. 2017; 25(4):404–409.^Citation22
Cardiac	There is evidence that genetic variants associated with Long QT syndrome and Brugada syndrome contribute to SIDS mortality. There is evidence that arrhythmogenic- related genetic variants may contribute to SIDS mortality in a multifactorial mode. There is evidence that genetic variants associated with cardiomyopathy (particularly HCM, LNVC, and restrictive cardiomyopathies) exist in SIDS cohorts and contribute to SIDS mortality.	Schwartz PJ et al N Engl J Med. 1998; 338(24):1709–14.^Citation31 Tester DJ et al J Am Coll Cardiol. 2018; 71(11):1217–1227.^Citation52 Dettmeyer RB et al Forensic Sci Int. 2010; 194(1–3):e21–4.^Citation47 Davis AM et al Circ Arrhythm Electrophysiol. 2016; 9(6):e003859.^Citation43
Serotonin system	Decreased serotonergic receptor binding and decreased levels of serotonin and tryptophan hydroxylase 2 have been observed in the brainstem of SIDS cohorts (compared to controls). Animal models that replicate serotonin differences documented in SIDS cohorts have shown dysfunctional autoresuscitation and death, when challenged with an apneic event. There are no genetic variants known to directly cause these serotonergic differences in the brainstem.	Paterson DS et al JAMA. 2006; 296(17):2124–32.^Citation62 Dosumu-Johnson RT et al Elife. 2018; 7:e37857.^Citation65 Paterson DS. Respir Physiol Neurobiol. 2013; 189(2):301–14.^Citation66
Epilepsy	A high proportion of SIDS cases have a neuropathologic change called bilamination of the dentate gyrus, which is seen in temporal lobe epilepsy. There is some evidence that genetic variants related to epilepsy exist in SIDS cohorts, although epilepsy genes have not been thoroughly interrogated in SIDS cohorts.	Kinney HC et al Acta Neuropathol. 2015;129(1):65–80.^Citation75 Brownstein CA et al Epilepsia. 2018; 59(4):e56–e62.^Citation84
Inflammation	A high proportion of SIDS cases have mild illness and an activated immune system at the time of death. Case-control studies have demonstrated a burden of inflammation related genetic polymorphisms in SIDS cases, although no monogenic genetic variants have been identified that would directly cause death.	Opdal SH. Cytokines, Infection, and Immunity. In: Duncan JR and Byard RW, editors. SIDS Sudden infant and early childhood death: The past, the present and the future. The University of Adelaide: University of Adelaide Press; 2018: 689–710.^Citation106
Ultrarare genetic conditions/syndromes	Several published case reports implicate ultrarare genetic conditions in SIDS cases. Most genetic studies of SIDS cohorts employ gene panel testing without inclusion of parental data, which hinders the ability to diagnose ultrarare genetic conditions.	Slater B et al Am J Med Genet. 2020 Sep 4.^Citation121 Byring RF et al Neuromuscul Disord. 2002; 12(6):548–53.^Citation125

Emery JL, Howat AJ, Variend S, Vawter GF. Investigation of inborn errors of metabolism in unexpected infant deaths. Lancet. 1988;2(8601):29–31. doi:10.1016/S0140-6736(88)92955-8

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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(4):404–409. doi:10.1038/ejhg.2016.199

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Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med. 1998;338(24):1709–1714. doi:10.1056/NEJM199806113382401

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Tester DJ, Wong LCH, Chanana P, et al. Cardiac genetic predisposition in sudden infant death syndrome. J Am Coll Cardiol. 2018;71(11):1217–1227. doi:10.1016/j.jacc.2018.01.030

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Dettmeyer RB, Kandolf R. Cardiomyopathies–misdiagnosed as Sudden Infant Death Syndrome (SIDS). Forensic Sci Int. 2010;194(1–3):e21–4. doi:10.1016/j.forsciint.2009.10.010

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Davis AM, Glengarry J, Skinner JR. Sudden infant death: QT or not QT? that is no longer the question. Circ Arrhythm Electrophysiol. 2016;9(6):e003859. doi:10.1161/CIRCEP.115.003859

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Paterson DS, Trachtenberg FL, Thompson EG, et al. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. JAMA. 2006;296(17):2124–2132. doi:10.1001/jama.296.17.2124

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Dosumu-Johnson RT, Cocoran AE, Chang Y, Nattie E, Dymecki SM. Acute perturbation of Pet1-neuron activity in neonatal mice impairs cardiorespiratory homeostatic recovery. Elife. 2018;7:e37857. doi:10.7554/eLife.37857

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Paterson DS. Serotonin gene variants are unlikely to play a significant role in the pathogenesis of the sudden infant death syndrome. Respir Physiol Neurobiol. 2013;189(2):301–314. doi:10.1016/j.resp.2013.07.001

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Kinney HC, Cryan JB, Haynes RL, et al. Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability. Acta Neuropathol. 2015;129(1):65–80. doi:10.1007/s00401-014-1357-0

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Brownstein CA, Goldstein RD, Thompson CH, et al. SCN1A variants associated with sudden infant death syndrome. Epilepsia. 2018;59(4):e56–e62. doi:10.1111/epi.14055

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Opdal SH. Cytokines, Infection, and Immunity. In: Duncan JR, Byard RW, editors. SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future. The University of Adelaide: University of Adelaide Press; 2018:689–710.

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Slater B, Glinton K, Dai H, et al. Sudden infant death with dysgenesis of the testes syndrome in a non-Amish infant: a case report. Am J Med Genet. 2020;182(11):2751–2754. doi:10.1002/ajmg.a.61842

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Byring RF, Pihko H, Tsujino A, et al. Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. Neuromuscul Disord. 2002;12(6):548–553. doi:10.1016/S0960-8966(01)00336-4

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