The Genetics of Sudden Infant Death Syndrome—Towards a Gene Reference Resource

Abstract

Sudden infant death syndrome (SIDS) is the unexpected death of an infant under one year of age that remains unexplained after a thorough investigation. Despite SIDS remaining a diagnosis of exclusion with an unexplained etiology, it is widely accepted that SIDS can be caused by environmental and/or biological factors, with multiple underlying candidate genes. However, the lack of biomarkers raises questions as to why genetic studies on SIDS to date are unable to provide a clearer understanding of the disease etiology. We sought to improve the identification of SIDS-associated genes by reviewing the SIDS genetic literature and objectively categorizing and scoring the reported genes based on the strength of evidence (from C1 (high) to C5 (low)). This was followed by analyses of function, associations between genes, the enrichment of gene ontology (GO) terms, and pathways and gender difference in tissue gene expression. We constructed a curated database for SIDS gene candidates consisting of 109 genes, 14 of which received a category 4 (C4) and 95 genes received the lowest category of C5. That none of the genes was classified into the higher categories indicates the low level of supporting evidence. We found that genes of both scoring categories show distinct networks and are highly diverse in function and involved in many GO terms and pathways, in agreement with the perception of SIDS as a heterogeneous syndrome. Genes of both scoring categories are part of the cardiac system, muscle, and ion channels, whereas immune-related functions showed enrichment for C4 genes. A limited association was found with neural development. Overall, inconsistent reports and missing metadata contribute to the ambiguity of genetic studies. Considering those parameters could help improve the identification of at-risk SIDS genes. However, the field is still far from offering a full-pledged genetic test to identify at-risk infants and is still hampered with methodological challenges and misunderstandings of the vulnerabilities of vital biological mechanisms.

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

“…A common feature of all these disorders (except the short or sometimes medium chain) is fasting hypoketotic hypoglycemia [ 8 , 9 ]. Approximately 5% of sudden deaths in childhood are secondary to FAODs [ 10 ], most of which are diagnosed postmortem. With the implementation of newborn screening, the clinical presentation and its natural history have changed significantly.…”

Non-polyalanine repeat mutation in PHOX2B is detected in autopsy cases of sudden unexpected infant death

“…SIDS/SUID risk is still likely defined by multifactorial genetic and environmental interactions [23,24]. In one of such subjects, we detected the missense mutation in PHOX2B.…”

Home Cardiorespiratory Monitoring in Infants at Risk for Sudden Infant Death Syndrome (SIDS), Apparent Life-Threatening Event (ALTE) or Brief Resolved Unexplained Event (BRUE)

“…Studies have shown that, compared to controls, SIDS children have more frequent significant abnormalities of both the serotonin transporter gene [17,18] and the monoamine oxidase gene [19,20], leading to decreased serotonergic receptor binding and reduced serotonin and tryptophan hydroxylase 2 levels in the brainstem with poor function of the autonomic nervous system. Moreover, alterations in genes encoding for cardiac ion channels [21,22], proteins involved in myocardial conduction [23], skeletal muscle sodium channels [24], several immune components (complement component C4, interleukin-10 promoter) [25,26], and heat shock proteins [27] have been reported. All of these findings suggest that SIDS prone children have significant differences in several body functions with poor response in front of lifethreatening conditions.…”