Genetics of Sudden Unexpected Death in Pediatrics

儿科意外猝死的遗传学

• 批准号: 9766340
• 负责人: Richard Daniel Goldstein
• 金额: $ 22.13万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766340
• 关键词: 1 year old; 3 year old; Accounting; Address; Affect; Age; Anatomy; Arrhythmia; Autopsy; Back to Sleep; Biochemical Markers; Biological Factors; Birth Records; Boston; Brain; Brain Stem; Cardiac; Cardiomyopathies; Cause of Death; Cessation of life; Child; Child Mortality; Childhood; Clinical; Collaborations; Complex; Data; Development; Diagnostic; Discipline of obstetrics; Disease; Early Diagnosis; Environment; Epilepsy; Etiology; Family; Febrile Convulsions; Fetus; Forensic Medicine; Foundations; Funding; Future; Genes; Genetic; Genetic Markers; Genomics; Heart Diseases; Hippocampus (Brain); Infant; Infant Mortality; Inherited; Intervention; Investigation; Lesion; Malignant Childhood Neoplasm; Massachusetts; Medical; Medical Examiners; Metabolic; Metabolic Diseases; Modeling; Molecular; National Institute of Child Health and Human Development; Neurologic; Parents; Pathogenicity; Pathologic; Pathway interactions; Pediatric Hospitals; Pediatric Research; Pediatrics; Penetrance; Phenotype; Physiological; Play; Population; Predisposition; Process; Proteins; Rare Diseases; Recording of previous events; Research; Research Priority; Risk; Risk Factors; Role; Science; Seizures; Serotonin; Sleep; Sudden Death; Sudden infant death syndrome; Testing; Uncertainty; United States; United States National Institutes of Health; Variant; base; cohort; exome; exome sequencing; falls; genetic analysis; genetic approach; genetic architecture; genetic variant; imaging study; innovation; insight; interdisciplinary approach; malformation; mortality; novel; phenotypic data; population based; potential biomarker; power analysis; prediction algorithm; predictive test; pressure; proband; programs; respiratory; risk minimization; trait

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.

项目摘要 婴儿猝死综合症(SID)和儿童原因不明猝死(SUDC)，我们 在儿科猝死(SUDP)的标题下共同研究，是婴儿的主要原因 和儿童死亡率。虽然安全睡眠的努力旨在将小岛屿发展中国家睡眠环境中的风险降至最低，但它是 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 猝死。随着外部因素的解决，SUDP的持久性证明了 这些内在的弱点。 长期以来，糖耐量低减一直被认为是“特发性的”，就像其他疾病一样，难以捉摸，可能是多因素的。 病因学。我们小组将SUDP视为一系列未诊断的疾病。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、 呼吸和感染机制，这些机制有一个可发现的遗传基础。我们 采取多学科方法，反映未诊断的疾病计划，包括广泛的表型和 全面的基因组分析，以确定导致SUDP的未知疾病机制。我们的 该小组此前曾在小岛屿发展中国家婴儿的脑干中发现5-羟色胺缺乏， 我们的诊断方法增加了小儿麻痹症和小儿麻痹症的可能性。 在对这些死亡儿童的评估中牵涉到自然原因。对这一应用的研究 寻求关于新基因和基因组机制的初步数据，这些基因和基因组机制导致猝死 由我们节目的表型方法提供信息的分析。 这项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。 这一假说将通过结合来自SUDP病例的丰富表型数据和外显子组测序来实现 分析。我们将确定并综合表型SUDP病例及其家属(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(目标2)相关。这项研究的一个非常新颖的方面是获得人口的机会- 基于洞察力，由于我们与 马萨诸塞州首席法医办公室(OCME)评估所有突然死亡的儿童和 在马萨诸塞州出人意料地未满3岁。 这项研究的潜在影响是阐明了突发性心脏病的遗传机制。 三岁以下儿童不明原因死亡。这项研究带来了进一步的前景： 有助于提高有SUDP风险的婴儿的特定预测算法和遗传标记， 以及推进法医分子尸检，以确定主要死亡原因。初步数据 本研究所取得的成果将有助于在未来的研究中进一步完善假设。