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

Abstract

Sudden Infant Death syndrome" (SIDS) represents the commonest category of infant death after the first month of life. As genome scale sequencing greatly facilitates the identification of new candidate disease variants, the challenges of ascribing causation to these variants persists. In order to determine the extent to which SIDS occurs in related individuals and their pedigree structure we undertook an analysis of SIDS using the Utah Population Database, recording, for example, evidence of enrichment for genetic causation following the back-to-sleep recommendations of 1992 and 1994. Our evaluation of the pre-and post back-to-sleep incidence of SIDS in Utah showed a decrease in SIDS incidence on the order of eightfold following back-to-sleep. An odds ratio of 4.2 for SIDS recurrence among sibs was identified from 1968 to 2013 which was similar to the odds ratio of 4.84 for death due to other or unknown cause among sibs of SIDS cases for the same time period. Combining first through thid degree relatives yielded an odds ratio of SIDS recurrence of 9.29 in the post-back-to-sleep (1995-2013) subset of SIDS cases where similar calculations of first-third degree relatives for the entire time period of 1968-2013 showed an odds ratio of 2.95. Expanded multigenertional pedigrees showing enrichment for SIDS were also identified. Based on these findings we hypothesize that post back-to-sleep SIDS, especially recurrences within a family, are potentially enriched for genetic causes due to the impact of safe sleeping guidelines in mitigating environmental risk factors.

Genetic Determinants of Sudden Unexpected Death in Pediatrics

“…7,8 Genetic contributions to SUDP are supported by studies of families whose children died from SIDS during the "safe sleep" era, which showed an increased risk for recurrence in subsequent siblings (odds ratio, [OR], 4.2) and within 3 generations (OR, 9.3). 9 The prevailing etiologic model of SUDP postulates that modest extrinsic threats become fatal in infants and children who harbor intrinsic vulnerabilities. 10 Early research described intrinsic vulnerabilities as biologically mediated risk factors such as prematurity, male sex, and prenatal alcohol and/or tobacco exposure.…”

The fundamental need for unifying phenotypes in sudden unexpected pediatric deaths

“…In this regard, the lingering influence of "Meadow's Law" (89) impedes the discovery of genetic diseases. Familial recurrence studies generate odds ratios of 4.84 for SIDS and other or unknown deaths to sibs at any age or an odds ratio of 9.29 (CI 2.62-32.96) in first through third degree relatives (90). Effects of this magnitude are typically seen with Mendelian disorders or conditions with directly causal environmental influences.…”