Genes disrupted by balanced genomic rearrangements in autism spectrum disorders

描述（由申请人提供）：广泛接受广泛性发育障碍谱系的强烈遗传贡献，但遗传因素在遗传能力的很大一部分仍然难以捉摸。最近在复杂疾病的遗传研究中取得的成功采取了两条不同的途径。第一项研究使用全基因组关联范式评估了常见变异。这种设计在异质疾病模型（如炎症性肠病和II型糖尿病）中取得了进展，但在识别复杂神经精神疾病（如精神分裂症）的风险位点方面却不太成功。第二种是利用先进的技术来提出常见病的罕见变异假说。在最近的研究中，导致遗传物质净增加或损失的结构变异与几种神经精神表型有关，这表明神经发育途径可能对基因剂量效应特别敏感。很明显，自闭症谱系障碍（ASD）的一部分遗传风险可归因于这些基因组事件，大量正在进行的常见多态性和罕见异常研究的高潮可能会为自闭症谱系障碍的一部分遗传风险提供重要的见解。这两种方法都没有明确解决的问题是均衡的染色体重排所带来的机会。这些事件在ASD患者中的发生率大大增加，但其影响在很大程度上是未知的，因为目前的基因分型方法无法准确检测这些事件。未能适当考虑ASD患者的这一亚组可能会忽略疾病变异的重要组成部分和确定致病途径的补充机会，特别是如果它针对的是不同的遗传贡献，而不是常见的多态性或剂量变化。正是在这个相对未被探索的领域，我们试图对理解ASD发病机制的遗传基础做出贡献。我们建议利用“新一代”测序的最新进展来鉴定染色体重排明显平衡的ASD患者中被破坏的基因。这些方法将建立在癌症遗传学的创新之上，为分析异常的种系核型定制它们。我们不断发展的方法也将有助于检测小拷贝数变异，这是研究人员正在努力表征的另一个模糊的基因组变异来源。该提案还将通过进行二级分子分析来确定疾病易感性的致病机制，而不是仅根据患者和对照队列中的新发状态或基因组事件的频率来推测致病性，从而与当前的基因组工作区分开来。研究将从我们合作的大量易位ASD患者的丰富资源开始，通过核型分析确定易位，并最终确定一系列未来生物学和药理学研究目标。

DESCRIPTION (provided by applicant): A strong genetic contribution to the spectrum of pervasive developmental disorders is widely accepted, yet genetic factors underlying a substantial portion of the heritability remain elusive. Recent successes in genetic studies of complex disorders have taken two divergent paths. The first has evaluated common variants using a genome wide association paradigm. This design has yielded progress in heterogeneous disease models such as inflammatory bowel disease and type II diabetes, but has been less successful in identifying risk loci for complex neuropsychiatric conditions such as schizophrenia. The second has used advancing technology to invoke the rare variant hypothesis of common disease. Structural variations resulting in a net gain or loss of genetic material have been associated with several neuropsychiatric phenotypes in recent studies, suggesting that neurodevelopment pathways may be particularly sensitive to gene dosage effects. It has become clear that a proportion of the genetic risk for autism spectrum disorders (ASD) is attributable to such genomic events, and the culmination of numerous ongoing studies of common polymorphisms and rare anomalies will likely provide important insight into a portion of genetic risk for ASDs. What is not clearly addressed by either approach is the opportunity presented by balanced chromosomal rearrangements. Estimates of the incidence of such events are substantially increased in ASD patients, yet their impact is largely unknown as current genotyping methods preclude accurate detection of these events. Failure to appropriately consider this subgroup of ASD patients potentially bypasses an important component of the disease variance and a complementary opportunity for determining causative pathways, particularly if it targets different genetic contributions than either common polymorphism or dosage variation. It is within this relatively unexplored space that we seek to contribute to understanding the genetic basis of ASD pathogenesis. We propose to use recent advances in "next-generation" sequencing to identify genes disrupted in ASD patients with apparently balanced chromosomal rearrangements. The methods will build upon innovations in cancer genetics, customizing them for analysis of abnormal germline karyotypes. Our evolving methodology will also facilitate detection of small copy number variations, another nebulous source of genomic variation that researchers are struggling to characterize. The proposal will also be set apart from current genomic efforts by conducting secondary molecular analysis to define the pathogenic mechanism of disease susceptibility rather than to speculate upon the pathogenicity solely from de novo status or from frequency of the genomic event in patient and control cohorts. The studies will begin with the rich resource currently available within our collaborations of a significant number of ASD patients with translocations identified by karyotype analysis and culminate in characterization of a series of future targets for biological and pharmacological investigation. PUBLIC HEALTH RELEVANCE: It has become clear that a proportion of the genetic risk for autism spectrum disorders (ASD) is attributable to both common polymorphisms and rare structural variations. What is not clearly addressed by current approaches is the opportunity presented by balanced chromosomal rearrangements. Estimates of the incidence of such events are substantially increased in ASD patients compared to the general population, yet their impact is largely unknown as current methodology precludes rapid and accurate detection of these genomic events. Failure to appropriately consider this subgroup of ASD patients potentially bypasses an important component of the disease variance and a complementary opportunity for determining causative pathways. It is within this relatively unexplored space that we seek to contribute to understanding the genetic basis of ASD pathogenesis. We propose to use recent advances in "next-generation" sequencing to identify genes disrupted in ASD patients with apparently balanced chromosomal rearrangements. The methodology will also enable assessment of small copy number variations, another seemingly intractable source of genetic variation. Secondary molecular analysis will then be used to define the pathogenic mechanisms rather than speculate on causation. The studies will begin with the rich resource currently available within our collaborations of a significant number of ASD patients with apparently overlapping rearrangement breakpoints identified by karyotype analysis and culminate in characterization of a series of future targets for biological and pharmacological investigation.