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):29–31.23 Neubauer J et al Eur J Hum Genet. 2017; 25(4):404–409.22
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):1709–14.31 Tester DJ et al J Am Coll Cardiol. 2018; 71(11):1217–1227.52 Dettmeyer RB et al Forensic Sci Int. 2010; 194(1–3):e21–4.47 Davis AM et al Circ Arrhythm Electrophysiol. 2016; 9(6):e003859.43
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):2124–32.62 Dosumu-Johnson RT et al Elife. 2018; 7:e37857.65 Paterson DS. Respir Physiol Neurobiol. 2013; 189(2):301–14.66
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):65–80.75 Brownstein CA et al Epilepsia. 2018; 59(4):e56–e62.84
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: 689–710.106
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 4.121 Byring RF et al Neuromuscul Disord. 2002; 12(6):548–53.125