Cardiac Channel Mutations in SIDS

SIDS 中的心脏通道突变

• 批准号: 9061431
• 负责人: MICHAEL JOHN ACKERMAN
• 金额: $ 53.64万
• 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/9061431
• 关键词: 1 year old; African American; Age-Months; Arrhythmia; Asians; Autistic Disorder; Autonomic nervous system; Biological; Brugada syndrome; Calcium; Candidate Disease Gene; Cardiac; Catecholaminergic Polymorphic Ventricular Tachycardia; Caucasians; 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; Genetic study; Genomics; Goals; Haploidy; Health; 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; Serotonergic System; Signal Transduction; Sodium; Sudden Death; Sudden infant death syndrome; Susceptibility Gene; Syndrome; System; Systems Biology; Technology; Testing; United States; 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; rare variant; research study; response; stem; trait; whole genome

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。为了达到NICHD根除这种情感破坏性综合征的最终目标，了解这种多因素综合征的潜在病因和发病机制至关重要。然而，对小岛屿发展中国家的根本原因仍然知之甚少。猝死的潜在遗传易感性，涉及中枢神经系统和血清素能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，可能是“婴儿易感性”的致病底物，与SIDS三重风险假说一致。小岛屿发展中国家的遗传很可能是多基因的和复杂的，但还没有进行研究来阐明“全球”遗传负荷。通过使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），我们的广泛目标是对世界上最大的多种族SIDS队列之一进行首次全基因组调查(n=625；303名高加索人，203名非裔美国人，96名西班牙人，14名亚洲人和9名混血儿)，目的是为了1)通过对SIDS病例-父母三人组进行aCGH和WES，探索小岛屿发展中国家受害者中根治新生突变（DNM）率增加的新概念，作为解释SIDS在世界范围内持续流行的一个范式转变；2)建立拷贝数变异（CNV）的谱、流行率和生物学途径参与，作为SIDS潜在的遗传易感性。3)利用WES和罕见非同义性遗传变异基因的通路/网络分析，建立跨多学科的“婴儿易感性遗传蓝图”，以确定特定的小岛屿发展障碍相关的分子生物学途径（如血清素能途径、免疫反应缺陷、心脏复极异常等）或信号网络是否受到主要影响。本实验将验证我们的三重假设：1)在新的小岛屿发展中国家易感基因和途径中发现具有明确功能意义的罕见DNM，以及潜在的DNM率，即小岛屿发展中国家非同义（NS）与同义DNM的比率，以及无意义与错义DNM的比率将超过之前在健康受试者中建立的比率；2)相当数量的小岛屿发展中国家病例是由于罕见的CNVs，典型表现为长度为1000个碱基的DNA片段的缺失和/或重复，这些缺失和/或重复改变了剂量的不平衡或神经发育、中枢神经系统信号、代谢、免疫和/或心脏通道病基因的破坏。3)小岛屿发展中国家的罕见遗传变异将过度分散到构成小岛屿发展中国家易感途径的基因上，“经典”（2至4个月大）小岛屿发展中国家在神经发育途径中携带罕见变异的负担增加，而“非经典”（<2个月或4个月大）小岛屿发展中国家在代谢、免疫或通道病变途径中携带罕见变异的负担增加。