Rapid characterization of balanced genomic rearrangements contributing to Autism

描述（由申请人提供）：个体化遗传医学的时代正在迅速到来。显着的技术进步带来了罕见的致病性变异的研究，在复杂疾病的研究中脱颖而出，重新定义的重点“风险变异”从人群为基础的队列到个体患者。这些研究已经将结构变异和复杂的基因组重排确定为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，目前的方法来映射这些变异仍然不精确，无法检测平衡重排和倒位，可能绕过一个高度信息化的患者亚组。这个奖学金旨在解决我们对基因组重排对神经发育异常的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”测序来鉴定被明显平衡重排破坏的基因。他们将建立在癌症遗传学的创新基础上，定制它们用于异常生殖细胞核型的分析。一个大规模并行配对末端策略的测序跳跃克隆将被用来首先映射精确的断点自闭症谱系障碍（ASD）患者与已知的基因组重排（目标I），然后进行全面的分子分析破坏基因（S）和途径（目标11）。依靠方法学优化，Aim 111将寻求筛选一个大型独立的ASD和其他疾病患者队列，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性方面依次建立，以解决重要且研究不足的患者队列。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，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。 公共卫生相关性：自闭症和相关神经发育障碍的遗传可能性很高，但遗传风险因素仍然不确定。由于技术限制，这些患者组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。

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.