Genetics of Sudden Unexpected Death in Pediatrics

项目摘要 婴儿猝死综合征（SIDS）和儿童期不明原因猝死（SUDC），我们 在儿科突然意外死亡（SUDP）的标题下一起研究，是婴儿死亡的主要原因。 和儿童死亡率。虽然安全睡眠的努力旨在最大限度地减少小岛屿发展中国家睡眠环境中的风险， 认识到受影响儿童也具有内在的脆弱性， 突然死亡由于外部因素已得到解决，持续存在的初级发展方案证明， 这些内在的脆弱性。 SUDP长期以来被认为是“特发性的”，就像其他疾病一样， 病因学我们小组将SUDP视为一组未诊断疾病。我们假设 导致SUDP的内在生物学因素包括神经发育、癫痫相关、心脏、代谢 呼吸和感染机制，并且这些机制具有可解释的遗传基础。我们 采取多学科的方法，反映未诊断的疾病计划，广泛的表型， 全面的基因组分析，以确定未识别的疾病机制负责SUDP。我们 研究小组先前发现SIDS婴儿脑干中的血清素缺乏， SIDS和SUDC病例中的海马，并表明我们的诊断方法增加了 在对这些死亡儿童的评估中暗示自然原因。本申请的研究 通过一项研究，寻求关于猝死的新基因和基因组机制的初步数据。 分析由我们的程序的方法表型通知。 拟议的研究将调查复杂的遗传结构是否在SUDP中起主要作用。 这一假设将通过结合SUDP病例的丰富表型数据和外显子组测序来实现 分析.我们将全面确定SUDP病例及其家族的表型（目的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（目标2）相关。这项研究的一个非常新颖的方面是增加人口的机会- 基于洞察力，由于前所未有的法医学术伙伴关系，我们已经建立了与 马萨诸塞州首席医学检查官办公室（OCME）评估所有突然死亡的儿童， 在马萨诸塞州的一个未满3岁的孩子。 这项研究的潜在影响是阐明了参与突发性糖尿病的遗传机制。 三岁以下儿童的不明原因死亡。这项研究带来了进一步的希望， 有助于在特定的预测算法和遗传标记的进步，为婴儿在SUDP的风险， 并推进法医分子解剖以确定死亡的主要原因。初步数据 本研究所获得之研究结果，将有助于未来研究假设之完善。

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.