Cardiac Channel Mutations in SIDS

SIDS 中的心脏通道突变

• 批准号: 8576888
• 负责人: MICHAEL JOHN ACKERMAN
• 金额: $ 54.18万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-07 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576888
• 关键词: 1 year old; African American; Age-Months; Arrhythmia; Asians; Autistic Disorder; Autonomic nervous system; Biological; Calcium; Candidate Disease Gene; Cardiac; Caucasians; Caucasoid Race; Cause of Death; Cessation of life; Code; Complex; Copy Number Polymorphism; DNA; DNA Sequence; Discipline; Disease; Energy Metabolism Pathway; Ethnic Origin; Ethnic group; Etiology; Family; Genes; Genetic; Genetic Determinism; Genetic Load; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Goals; Haploidy; Heart; Hispanics; Immune System Diseases; Immune response; Immune system; Immunologics; Incidence; Infant; Ion Channel; Label; Length; Life; Long QT Syndrome; Macromolecular Complexes; Mental Retardation; Metabolic; Metabolism; Molecular; Mutation; National Institute of Child Health and Human Development; Nature; Neuraxis; Nicotine; Nucleotides; Parents; Pathogenesis; Pathogenicity; Pathway Analysis; Pathway interactions; Potassium; Predisposition; Prevalence; Race; Recording of previous events; Research; Risk; RyR2; Schizophrenia; Signal Transduction; Sodium; Sudden Death; Sudden infant death syndrome; Susceptibility Gene; Syndrome; System; Systems Biology; Technology; Testing; United States; Variant; Ventricular Tachycardia; base; cohort; comparative genomic hybridization; dosage; ethnic difference; exome; exome sequencing; genetic variant; genome-wide; high risk infant; infant death; insertion/deletion mutation; next generation; novel; public health relevance; research study; response; stem; trait

DESCRIPTION (provided by applicant): With over 2000 deaths each year in the United States, sudden infant death syndrome (SIDS) remains a leading cause of death in infants under 1 year of age. In order to reach the ultimate goal of the NICHD to eradicate this emotionally devastating syndrome, it is vital to understand the underlying etiologies and pathogenesis of this multifactorial syndrome. However, the fundamental causes of SIDS remain poorly understood. Underlying genetic susceptibility for sudden death, involving genetic determinants of the central nervous system and serotonergic signaling, immune dysfunction, metabolism/energy pathway, nicotine response, and cardiac repolarization, may represent pathogenic substrates for "infant vulnerability" in accordance with the SIDS triple risk hypothesis for a significant number of SIDS cases. The genetics of SIDS is most likely multigenic and complex yet there has been no studies performed to elucidate the "global" genetic load. Through the use of monumental technological advances in genomic research, including array comparative genomic hybridization (aCGH) and next-generation "whole- exome" DNA sequencing (WES), it is our broad objective to perform the first whole genome interrogation of one of the world's largest assembled, multi-ethnic SIDS cohorts (n=625; 303 Caucasian, 203 African American, 96 Hispanic, 14 Asian, and 9 mixed race) in order 1) to explore the novel concept of increased radical de novo mutation (DNM) rate among SIDS victims as a paradigm shift in explaining the paradoxical sustained world-wide prevalence of SIDS by performing aCGH and WES on SIDS case-parent trios, 2) to establish the spectrum, prevalence, and biological pathway involvement of copy number variations (CNV) as an underlying genetic susceptibility for SIDS, and 3) to establish a "Genetic Blueprint of Infant Vulnerability" across multiple disciplines using WES and pathway/network analysis of genes identified with rare non-synonymous genetic variants, to ascertain whether specific SIDS-associated molecular biological pathways (i.e. serotonergic pathways, immune response deficiencies, cardiac repolarization abnormalities, etc.) or signaling networks are predominantly effected. The proposed experiments will test our three-fold hypothesis that 1) rare DNMs with clear functional significance will be identified in novel SIDS-susceptibility genes and pathways and the underlying DNM rate, defined as the ratio of non-synonymous (NS) to synonymous DNMs, and the ratio of nonsense to missense DNMs in SIDS will exceed the ratio previously established in healthy living subjects, 2) a significant number of SIDS cases are due to rare CNVs typified as deletions and/or duplications of DNA segments of e 1kilobase in length that alter either imbalances of dosage or disruption of neurodevelopmental, CNS signaling, metabolic, immunologic, and/or cardiac channelopathic genes, and 3) rare genetic variants in SIDS will be over-dispersed to genes comprising SIDS-susceptibility pathways with "classical" (2 to 4 months of age) SIDS cases harboring an increase burden of rare variants in a neurodevelopmental pathways while "non-classical" (<2 months or > 4 months) SIDS cases will harbor an increased burden of rare variants in metabolic, immunologic, or channelopathic pathway(s).

描述（由申请人提供）：美国每年有超过 2000 人死亡，婴儿猝死综合症 (SIDS) 仍然是 1 岁以下婴儿死亡的主要原因。为了实现 NICHD 根除这种情绪破坏性综合症的最终目标，了解这种多因素综合症的潜在病因和发病机制至关重要。然而，人们对 SIDS 的根本原因仍知之甚少。猝死的潜在遗传易感性，涉及中枢神经系统和血清素信号的遗传决定因素、免疫功能障碍、代谢/能量途径、尼古丁反应和心脏复极，可能代表“婴儿脆弱性”的致病底物，符合大量 SIDS 病例的 SIDS 三重风险假说。 SIDS 的遗传学很可能是多基因且复杂的，但尚未进行任何研究来阐明“全局”遗传负荷。通过利用基因组研究中的重大技术进步，包括阵列比较基因组杂交 (aCGH) 和下一代“全外显子组”DNA 测序 (WES)，我们的总体目标是对世界上最大的多种族 SIDS 队列之一（n=625；303 名白种人、203 名非裔美国人、96 名西班牙裔、 14 名亚洲人，9 名混血人种），目的是 1）探索 SIDS 受害者中根本性从头突变（DNM）率增加的新概念，通过对 SIDS 病例父母三人组进行 aCGH 和 WES 来解释 SIDS 矛盾的持续全球患病率的范式转变，2）建立拷贝数变异（CNV）的谱系、患病率和生物途径参与 作为 SIDS 的潜在遗传易感性，3) 使用 WES 和对罕见非同义遗传变异鉴定的基因进行通路/网络分析，建立跨多个学科的“婴儿脆弱性遗传蓝图”，以确定特定的 SIDS 相关分子生物学通路（即血清素通路、免疫反应缺陷、心脏复极）是否与 SIDS 相关。 异常等）或信号网络主要受到影响。所提出的实验将检验我们的三重假设：1）在新的 SIDS 易感性基因和通路中将鉴定出具有明确功能意义的罕见 DNM，以及潜在的 DNM 率（定义为非同义（NS）与同义 DNM 的比率），以及 SIDS 中无义与错义 DNM 的比率将超过先前在健康生活受试者中建立的比率，2）大量 的 SIDS 病例是由于罕见的 CNV 造成的，典型的为长度为 1kb 的 DNA 片段的缺失和/或重复，这些 CNV 改变了剂量不平衡或神经发育、中枢神经系统信号传导、代谢、免疫和/或心脏通道病基因的破坏，并且 3) SIDS 中的罕见遗传变异将过度分散为以下基因： SIDS 易感性途径：“经典”（2 至 4 个月大）SIDS 病例的神经发育途径中罕见变异的负担增加，而“非经典”（<2 个月或 > 4 个月）SIDS 病例的代谢、免疫或通道病途径中罕见变异的负担增加。