Rapid characterization of balanced genomic rearrangements contributing to Autism

描述（由申请人提供）：个体化基因医学时代即将到来。显著的技术进步使对罕见致病变异的研究在复杂疾病的研究中脱颖而出，将“风险变异”的重点从基于人群的队列重新定义为个体患者。这些研究已经确定了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，这表明神经通路可能对融合基因和剂量效应特别敏感。然而，目前绘制这些变异的方法仍然不精确，无法检测到平衡的重排和倒置，可能会绕过一个信息丰富的患者亚组。这项研究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这一重大缺陷。本文提出的研究将使用“下一代”测序来识别被明显平衡重排破坏的基因。他们将以癌症遗传学的创新为基础，定制它们来分析异常的种系核型。测序跳跃克隆的大规模平行配对端策略将首先用于绘制已知基因组重排（Aim I）的自闭症谱系障碍（ASD）患者的精确断点，然后对中断基因(s)和途径（Aim 11）进行全面的分子分析。基于方法学的优化，Aim 111将寻求筛选一个被诊断为ASD和其他疾病的患者的大型独立队列，以确定一致的重排和/或新的罕见突变。因此，这些研究将在范围和复杂程度上依次建立，以解决一个重要的和未充分研究的患者群体。总的来说，它们可以在关注个体基因组的遗传风险方面取得重要进展，潜在地将基于基因型的分类作为儿科临床实践中实用的诊断工具。

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.