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 我们的猝死综合症（SIDS）和童年意外死亡（SUDC），我们 在小儿（SUDP）突然意外死亡的标题下一起研究，是婴儿的主要原因 和儿童死亡率。虽然安全的睡眠努力旨在最大程度地降低小岛屿发展中国家睡眠环境中的风险，但这是 认识到受影响的儿童还具有内在脆弱性，使他们的敏感性增加 猝死。由于已经解决了外部因素，SUDP的持续存在证明了 这些内在的漏洞。 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多因素的条件一样 病因。我们的小组将SUDP作为未诊断疾病的星座。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，这些机制具有可发现的遗传基础。我们 采用一种多学科的方法，可以反映未诊断的疾病计划，并具有广泛的表型和 全面的基因组分析以确定导致SUDP的未识别疾病机制。我们的 小组以前已经发现5-羟色胺在小米小熊婴儿的脑干中定义 SIDS和SUDC病例中的海马，并表明我们的诊断方法增加了 在评估这些已故儿童时，隐含的自然原因。该应用程序的研究 寻求有关新基因和通过猝死的基因组机制的初步数据 分析以我们计划的表型方法的方式告知。 拟议的研究将研究复杂的遗传结构在SUDP中是否起着重要作用。 通过将来自SUDP案例的丰富表型数据与外显子组测序相结合来提出这一假设 分析。我们将确定，全面的表型SUDP案件及其家人（AIM 1），然后 分析来自这些良好的概率和父母三重奏的外显子组数据，以确定遗传机制 与SUDP相关（AIM 2）。这项研究的一个高度新颖的方面是获得人口的机会 - 由于我们与该公司建立的前所未有的法医学学术伙伴关系，基于的见解 马萨诸塞州首席医学检查员办公室（OCME）评估所有突然死亡的儿童， 在马萨诸塞州出乎意料的3岁以下。 这项研究的潜在影响是阐明与突然有关的遗传机制 三岁以下儿童无法解释的死亡。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 并促进法医分子尸检，以建立死亡的主要原因。初步数据 在这项研究中获得的将导致在未来的研究中探索的假设的完善。