Rapid characterization of balanced genomic rearrangements contributing to Autism

快速表征导致自闭症的平衡基因组重排

• 批准号: 8010962
• 负责人: MICHAEL E TALKOWSKI
• 金额: $ 5.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010962
• 关键词: Accounting; Address; Autistic Disorder; Bypass; Child; Childhood; Classification; Complex; Cytogenetics; DNA Sequence Rearrangement; Data; Data Set; Detection; Diagnosis; Diagnostic; Disease; Environment; Equilibrium; Event; Fellowship; Gene Dosage; General Population; Genes; Genetic Medicine; Genetic Research; Genetic Risk; Genome; Genomics; Genotype; Goals; Heritability; Human Genetics; Incidence; Individual; Infant; Lead; Maps; Methodology; Methods; Modeling; Molecular; Molecular Analysis; Mutation; Neurodevelopmental Disorder; Neurologic; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Population; Proteins; Public Health; Recurrence; Resolution; Risk; Screening procedure; Site; Staging; Subgroup; Technology; Training; Variant; autism spectrum disorder; base; cancer genetics; clinical practice; cohort; cost effective; design; fusion gene; genetic risk factor; genome sequencing; genome wide association study; ilium; innovation; interest; neuropsychiatry; next generation; novel; novel diagnostics; population based; pre-doctoral; public health relevance; rapid technique; tool

DESCRIPTION (provided by applicant): The era of individualized genetic medicine is fast approaching. Remarkable technical advances have brought the search for rare pathogenic variants to the fore in studies of complex disorders, redefining the focus of 'risk variant' from the population based cohort to the individual patient. Such studies have identified structural variations and complex genomic rearrangements as key variants associated with autism and other neuropsychiatric phenotypes, suggesting neurological pathways may be particularly sensitive to fusion genes and dosage effects. Yet current methods to map such variants remain imprecise, unable to detect balanced rearrangements and inversions, potentially bypassing a highly informative patient subgroup. This fellowship intends to address this significant deficit in our understanding of the impact of genomic rearrangements on neurodevelopmental abnormalities. The studies proposed herein will use "next- generation" sequencing to identify genes disrupted by apparently balanced rearrangements. They will build upon innovations in cancer genetics, customizing them for analysis of abnormal germline karyotypes. A massively parallel paired-end strategy of sequencing jumping clones will be used to first map precise breakpoints in autism spectrum disorder (ASD) patients with known genomic rearrangements (Aim I), then conduct comprehensive molecular analysis of disrupted gene(s) and pathways (Aim 11). Relying on methodological optimization, Aim 111 will seek to screen a large independent cohort of patients diagnosed with ASD and other disorders to identify consistent rearrangements and/or novel rare mutations. These studies will thus sequentially build in both scope and sophistication to address an important and understudied patient cohort. Collectively, they could yield important progress in focusing genetic risk to the individual genome, potentially delivering genotype-based classification as a pragmatic diagnostic tool in pediatric clinical practice. Public Health Relevance: The heritability of autism and related neurodevelopmental disorders is high but contributing genetic risk factors remain uncertain. The true incidence of genomic rearrangements in these patient groups could be substantially underestimated due to technological limitations. Novel methods for rapid screening are therefore needed. These studies could facilitate new diagnostic classifications that account for individual genomic events, explain a meaningful proportion of disease variance that is currently unknown, and help elucidate causative pathways.

描述（申请人提供）：个体化基因医学时代正在迅速到来。显着的技术进步使得对罕见致病变异的寻找在复杂疾病的研究中脱颖而出，将“风险变异”的焦点从基于人群的队列重新定义为个体患者。此类研究已确定结构变异和复杂的基因组重排是与自闭症和其他神经精神表型相关的关键变异，表明神经通路可能对融合基因和剂量效应特别敏感。然而，目前绘制此类变异的方法仍然不精确，无法检测平衡的重排和倒位，可能会绕过信息丰富的患者亚组。该奖学金旨在解决我们对基因组重排对神经发育异常影响的理解中的重大缺陷。本文提出的研究将使用“下一代”测序来鉴定被明显平衡的重排破坏的基因。他们将建立在癌症遗传学创新的基础上，对其进行定制以分析异常种系核型。跳跃克隆测序的大规模并行双端策略将首先用于在已知基因组重排的自闭症谱系障碍 (ASD) 患者中绘制精确的断点图谱（目标 I），然后对破坏的基因和通路进行全面的分子分析（目标 11）。依靠方法学优化，Aim 111 将寻求筛查大量被诊断患有 ASD 和其他疾病的独立患者群体，以识别一致的重排和/或新的罕见突变。因此，这些研究将依次扩大范围和复杂程度，以解决重要且尚未得到充分研究的患者群体的问题。总的来说，它们可以在将遗传风险集中到个体基因组方面取得重要进展，有可能将基于基因型的分类作为儿科临床实践中的实用诊断工具。 公共健康相关性：自闭症和相关神经发育障碍的遗传性很高，但影响遗传风险因素仍不确定。由于技术限制，这些患者群体中基因组重排的真实发生率可能被大大低估。因此需要快速筛选的新方法。这些研究可以促进新的诊断分类，解释个体基因组事件，解释目前未知的疾病变异的有意义的比例，并帮助阐明致病途径。