Genetics of Sudden Unexpected Death in Pediatrics

项目概要 婴儿猝死综合症 (SIDS) 和儿童期不明原因猝死 (SUDC) 在儿科突然意外死亡（SUDP）的标题下一起研究，是婴儿意外死亡的一个主要原因 和儿童死亡率。虽然安全睡眠工作旨在最大限度地减少婴儿猝死综合症 (SIDS) 睡眠环境中的风险，但 认识到受影响的儿童也具有内在的脆弱性，这增加了他们对 突然死亡。随着外部因素的解决，SUDP 的持续存在证明了 这些内在的弱点。 SUDP 长期以来一直被认为是“特发性”，就像其他难以捉摸且可能是多因素影响的病症一样 病因学。我们小组将 SUDP 视为一组未确诊的疾病。我们假设 导致 SUDP 的内在生物因素包括神经发育、癫痫相关、心脏、代谢、 呼吸道和感染机制，并且这些机制具有可发现的遗传基础。我们 采取多学科方法，反映未诊断的疾病计划，并进行广泛的表型分析和 全面的基因组分析，以确定导致 SUDP 的未知疾病机制。我们的 研究小组此前发现 SIDS 婴儿的脑干存在血清素缺陷，大脑畸形 SIDS 和 SUDC 病例中的海马体，并表明我们的诊断方法增加了 对这些已故儿童的评估涉及自然原因。本申请的研究 通过一种方法寻求有关猝死背后的新基因和基因组机制的初步数据 我们的程序的表型分析方法为分析提供了信息。 拟议的研究将调查复杂的遗传结构是否在 SUDP 中发挥重要作用。 这一假设将通过将 SUDP 病例的丰富表型数据与外显子组测序相结合来实现 分析。我们将确定并全面分析 SUDP 病例及其家属的表型（目标 1），然后 分析这些表型良好的先证者父母三人组的外显子组数据，以确定遗传机制 与 SUDP 相关（目标 2）。这项研究的一个非常新颖的方面是获得人口的机会 基于我们与法医学术界建立的前所未有的合作伙伴关系 马萨诸塞州首席法医办公室 (OCME) 将评估所有突然死亡的儿童 出人意料的是，他在马萨诸塞州还不到 3 岁。 这项研究的潜在影响是阐明涉及突发事件的遗传机制 三岁以下儿童不明原因死亡。这项研究带来了进一步的希望 为有 SUDP 风险的婴儿的特定预测算法和遗传标记的进步做出贡献， 并推进法医分子尸检以确定死亡的主要原因。初步数据 这项研究中获得的成果将有助于完善未来研究中要探索的假设。

Project Summary Sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC), which we study together under the rubric of sudden unexpected death in pediatrics (SUDP), is a major cause of infant and child mortality. While Safe Sleep efforts aim to minimize risks in the sleep environment in SIDS, it is recognized that affected children also possess intrinsic vulnerabilities that increase their susceptibility to sudden death. As external factors have been addressed, the persistence of SUDP attests to the significance of these intrinsic vulnerabilities. SUDP has long been considered “idiopathic,” like other conditions with elusive and likely multifactorial etiologies. Our group approaches SUDP as a constellation of undiagnosed diseases. We hypothesize that the intrinsic biological factors leading to SUDP include neurodevelopmental, epilepsy-related, cardiac, metabolic, respiratory, and infectious mechanisms, and that these mechanisms have a discoverable genetic basis. We take a multidisciplinary approach that mirrors undiagnosed disease programs, with extensive phenotyping and comprehensive genomic analysis to identify unrecognized disease mechanisms responsible for SUDP. Our group has previously found serotonin deficits in the brainstem of SIDS infants, malformations of the hippocampus in SIDS and SUDC cases, and shown that our diagnostic approach increases the likelihood of implicating natural causes in the assessment of these deceased children. The research in this application seeks preliminary data on novel genes and genomic mechanisms underlying sudden death through an analysis informed by our program's approach to phenotyping. The proposed research will investigate whether a complex genetic architecture plays a major role in SUDP. This hypothesis will be pursued by combining rich phenotypic data from SUDP cases with exome sequencing analysis. We will ascertain and comprehensively phenotype SUDP cases and their families (Aim 1), and then analyze exome data from these well-phenotyped proband-parent trios, to determine genetic mechanisms associated with SUDP (Aim 2). A highly novel aspect of this research is the opportunity to gain population- based insights due to the unprecedented forensic-academic partnership we have established with the Massachusetts Office of the Chief Medical Examiner (OCME) to assess all children dying suddenly and unexpectedly under the age of 3 years in Massachusetts. The potential impact of this research is the elucidation of genetic mechanisms involved in sudden unexplained deaths in children under the age of three years. This research carries the further promise of contributing to advancements in specific predictive algorithms and genetic markers for infants at risk for SUDP, and advancing the forensic molecular autopsy in establishing a major cause of mortality. The preliminary data gained in this research will lead to the refinement of hypotheses to be explored in future research.