Systems-level perspective of sudden infant death syndrome

Abstract

Sudden Infant Death Syndrome (SIDS) remains one of the primary causes of infant mortality in developed countries. While the causes of SIDS remain largely inconclusive, some of the most informative associations implicate molecular, genetic, anatomical, physiological and environmental (i.e., infant sleep) factors. Thus, a comprehensive and evolving systems-level model is required to understand SIDS susceptibility. Such models, by being powerful enough to uncover indirect associations, could be used to expand our list of candidate targets for in-depth analysis. We present an integrated WikiPathways model for SIDS susceptibility that includes associated cell systems, signaling pathways, genetics and animal phenotypes. Experimental and literature-based gene-regulatory data has been integrated into this model, to identify intersecting upstream control elements and associated interactions. To expand this pathway model, we performed a comprehensive analysis of existing proteomics data from brainstem samples of SIDS infants. From this analysis, we discovered changes in the expression of several proteins linked to known SIDS pathologies, including factors involved in glial cell production, hypoxia regulation, and synaptic vesicle release, in addition to interactions with annotated SIDS markers. Our results highlight new targets for further consideration that further enrich this pathway model, which, over time, can improve as a wiki-based, community curation project.

Noncardiac genetic predisposition in sudden infant death syndrome

“…While there have been no clear diagnostic markers identified, several common polymorphism have been identified to be significantly over-represented in distinct SIDS ethnic populations. 8 Recently, we completed exome sequencing-based molecular autopsy with a genetic heart disease (GHD) gene-specific analysis for 278 unrelated European ancestry SIDS cases in order to determine the contribution of monogenic heart disease to SIDS pathology. Less than 12% of the European SIDS cases hosted an ultra-rare (MAF < 0.005%) "potentially informative" variant in one of the 90 GHD-susceptibility genes analyzed.…”

“…A list of 55 SIDS-susceptibility genes involving multiple, non-cardiac biological pathways implicated previously in SIDS pathogenesis was derived from Salomonis' Integrated Mechanism Review article, "Systems-level perspective of Sudden Infant Death Syndrome" published in 2014. 8 This literature review based list included genes with sufficient evidence for involvement of SIDS based on the reported conclusions of manuscript authors. 8 Based on our own literature search of articles from 2014 to 2018, 6 additional SIDS-susceptibility genes were included for a total list of 61 non-cardiac, candidate genes (see Online Supplement eTable 1).…”

“…8 This literature review based list included genes with sufficient evidence for involvement of SIDS based on the reported conclusions of manuscript authors. 8 Based on our own literature search of articles from 2014 to 2018, 6 additional SIDS-susceptibility genes were included for a total list of 61 non-cardiac, candidate genes (see Online Supplement eTable 1). [17][18][19][20][21] Following exome sequencing, single nucleotide variants (SNVs) and insertion/deletions (INDELs) were filtered to identify variants which followed either a dominant or recessive inheritance pattern using Ingenuity Variant Software (Qiagen, Redwood City, CA).…”

“…3 Rather than a single etiology underlying the majority of infant vulnerability, SIDS may be due to multiple distinct genetic disorders with a common final endpoint of sudden death occurring during sleep. 8 Several studies have implicated both common and rare genetic variants within genes involved in several biological pathways including neurological conditions, neuronal signaling, inborn errors of metabolism, respiratory control, musculoskeletal conditions, immune response, and genetic heart disease (GHD) as a basis for underlying infant vulnerability. 2,[9][10][11][12][13][14] Using exome sequencing and a targeted analysis of 90 GHD-susceptibility genes in over 400 SIDS cases, we determined recently a 5% prevalence of GHD-associated "pathogenic" or "likely pathogenic" variants as a potential monogenic basis for SIDS.…”

Sudden infant death “syndrome”—Insights and future directions from a Utah population database analysis

“…By definition, autopsy and environmental review are unrevealing; however, more or less subtle signs of asphyxiation suggest in some cases a sleep respiratory component. Contemporary working models of SIDS pathogenesis are based on SIDS as an entity of infancy manifesting in the developmentally at‐risk infant in the setting of possible environmental stresses [Salomonis, ]. However, this model could be expanded to envision heritable forms of SIDS as the early end of a sudden death phenotype possibly extending beyond infancy.…”