Cardiac Channel Mutations in SIDS

描述(申请人提供)：在美国，每年有2000多人死亡，婴儿猝死综合症(SID)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，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5-羟色胺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，根据小岛屿发展中国家三重风险假说，在相当数量的小岛屿发展中国家病例中，这些可能是“婴儿易感性”的致病底物。小岛屿发展中国家的遗传学很可能是多基因和复杂的，但还没有进行过任何研究来阐明“全球”的遗传负荷。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组装的、多种族的小岛屿发展中国家队列之一进行第一次全基因组询问(n=625；303名高加索人，203名非裔美国人，96名西班牙裔，14名亚洲人和9名混合种族)，目的是1)通过对SID病例-父母三人组进行aCGH和WES，探索SID患者中新生突变(DNM)增加的新概念，作为解释SID矛盾的持续全球流行的范式转变，2)建立拷贝数变异(CNV)作为SID潜在遗传易感性的谱、流行和生物途径参与，以及3)使用WES和罕见的非同义遗传变异识别的基因的路径/网络分析，建立跨多学科的婴儿脆弱性遗传蓝图，以确定特定的小岛屿发展中国家相关分子生物学途径(即5-羟色胺能途径、免疫反应缺陷、心脏复极异常等)。或者信令网络主要受到影响。拟议的实验将检验我们的三重假设：1)在新的小岛屿发展中国家易感基因和途径中将识别出具有明显功能意义的罕见DNM，潜在的DNM率，定义为非同义DNM与同义DNM的比率，并且SID中无意义和错义DNM的比率将超过先前在健康受试者中建立的比率；2)相当多的SID病例是由于罕见的CNV，其典型表现为1kb碱基DNA片段的缺失和/或复制，改变了神经发育、CNS信号、代谢、免疫学和/或心脏通道病变基因的剂量失衡或中断3)小儿麻痹症中罕见的遗传变异将过度分散到构成小儿麻痹症易感途径的基因中，典型的(2至4个月龄)小儿麻痹症病例在神经发育途径中的罕见变异的负担增加，而非典型的(&lt；2个月或4个月)小岛屿发展中国家患者的代谢、免疫学或通道病变途径中的罕见变异的负担将增加(S)。

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).