Rapid characterization of balanced genomic rearrangements contributing to Autism

描述(申请人提供)：个性化基因医学时代正在迅速到来。显著的技术进步使寻找罕见的致病变异成为复杂疾病研究的首要任务，重新定义了“风险变异”的重点，从基于人群的队列到单个患者。这些研究已经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，目前定位这些变异的方法仍然不精确，无法检测到平衡的重排和颠倒，潜在地绕过了高度信息量的患者亚群。该奖学金旨在解决我们在了解基因组重排对神经发育异常的影响方面的这一重大缺陷。这里提出的研究将使用“下一代”测序来识别被明显平衡的重排打乱的基因。他们将建立在癌症遗传学创新的基础上，定制它们以分析异常的生殖系核型。一种大规模平行的成对末端跳跃克隆测序策略将首先在已知基因组重排的自闭症谱系障碍患者中绘制精确的断裂点图谱(目标I)，然后对中断基因(S)和通路进行全面的分子分析(目标11)。依靠方法学优化，AIM 111将寻求对大量被诊断为ASD和其他疾病的患者进行独立队列筛选，以确定一致的重排和/或新的罕见突变。因此，这些研究将按顺序建立范围和复杂性，以解决重要的和未被研究的患者队列。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，潜在地将基于基因的分类作为儿科临床实践中的一种实用诊断工具。 公共卫生相关性：自闭症和相关神经发育障碍的遗传率很高，但导致遗传风险的因素仍然不确定。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，需要新的快速筛查方法。这些研究可以促进新的诊断分类，解释个别基因组事件，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.