Cardiac Channel Mutations in SIDS

描述（由申请人提供）：在美国，每年有超过2000例死亡，婴儿猝死综合征（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肾上腺素能信号传导的遗传决定因素、免疫功能障碍、代谢/能量途径、尼古丁反应和心脏复极化，可能代表“婴儿脆弱性”的致病基质，这与SIDS三重风险假说一致，适用于大量SIDS病例。小岛屿发展中国家的遗传学很可能是多基因和复杂的，但还没有进行研究，以阐明“全球”的遗传负荷。通过利用基因组研究中的巨大技术进步，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小岛屿发展中国家群体之一进行首次全基因组调查（n=625; 303名白人，203名非裔美国人，96名西班牙裔，14名亚洲人，和9个混合种族），目的是1）探索小岛屿发展中国家受害者中增加的激进从头突变（DNM）率的新概念，作为解释矛盾的持续世界的范式转变-通过对SIDS病例-父母三人组进行aCGH和WES，确定SIDS的广泛患病率，2）确定拷贝数变异（CNV）的谱、患病率和生物学途径参与作为SIDS的潜在遗传易感性，和3）使用WES和对鉴定出具有罕见非同义遗传变异的基因的通路/网络分析，建立跨多学科的“婴儿脆弱性遗传蓝图”，以确定是否存在特定的SIDS相关分子生物学途径（即β-肾上腺素能途径、免疫应答缺陷、心脏复极异常等）或者主要影响信令网络。所提出的实验将测试我们的三重假设，即1）在新的SIDS易感性基因和途径中将鉴定出具有明确功能意义的罕见DNM，并且潜在的DNM率（定义为非同义（NS）与同义DNM的比率）和SIDS中无义与错义DNM的比率将超过先前在健康活体受试者中建立的比率，2）大量SIDS病例是由于罕见的CNV，其典型表现为内皮素酶DNA片段长度的缺失和/或重复，其改变了剂量的不平衡或神经发育、CNS信号传导、代谢、免疫和/或心脏通道病变基因的破坏，和3）SIDS中的罕见遗传变异将过度分散到包含SIDS易感性途径的基因中，其中“经典”（2至4个月大）SIDS病例在神经发育途径中具有增加的罕见变异负担，而“非经典”（<2 months or >4个月大）SIDS病例将在代谢、免疫或通道病变途径中具有增加的罕见变异负担。

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).