Genes disrupted by balanced genomic rearrangements in autism spectrum disorders

描述(由申请人提供)：普遍发育障碍的谱系中有很强的遗传因素已被广泛接受，然而很大一部分遗传性的遗传因素仍然难以捉摸。最近在复杂疾病的遗传学研究中取得的成功采取了两条不同的道路。第一项研究使用全基因组关联范式评估了常见的变异。这一设计在炎症性肠病和II型糖尿病等异质疾病模型方面取得了进展，但在识别复杂神经精神疾病(如精神分裂症)的风险基因方面不太成功。第二种是使用先进的技术来引用常见疾病的罕见变异假说。在最近的研究中，导致遗传物质净增加或损失的结构变化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)的遗传风险有一部分可归因于此类基因组事件，而对常见多态和罕见异常的大量正在进行的研究的结果可能会为了解ASD的一部分遗传风险提供重要的见解。任何一种方法都没有明确解决的是平衡的染色体重排带来的机会。在ASD患者中，对此类事件发生率的估计大幅增加，但它们的影响在很大程度上是未知的，因为目前的基因分型方法排除了对这些事件的准确检测。如果不能适当地考虑ASD患者的这一亚组，可能会绕过疾病变异的一个重要组成部分，以及确定致病途径的补充机会，特别是如果它针对的基因贡献不同于常见的多态或剂量变化。正是在这个相对未知的空间里，我们试图为理解ASD发病的遗传学基础做出贡献。我们建议使用“下一代”测序的最新进展来识别明显平衡的染色体重排的ASD患者中被破坏的基因。这些方法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。我们不断发展的方法论还将有助于检测小拷贝数变异，这是研究人员正在努力确定的另一个模糊的基因组变异来源。该提案还将有别于目前的基因组努力，通过进行二次分子分析来确定疾病易感性的致病机制，而不是仅从从头开始的状态或根据患者和对照队列中基因组事件的频率来推测致病性。这些研究将从我们与大量通过核型分析确定易位的ASD患者的合作中目前可用的丰富资源开始，并最终确定一系列未来生物学和药理学研究的目标。 与公共卫生相关：已经很明显，自闭症谱系障碍(ASD)的遗传风险的一部分可归因于常见的多态和罕见的结构变异。目前的方法没有明确解决的是平衡的染色体重排带来的机会。与普通人群相比，ASD患者中此类事件的发生率估计显著增加，然而它们的影响在很大程度上是未知的，因为目前的方法学排除了对这些基因组事件的快速和准确的检测。如果不能适当考虑ASD患者的这一亚组，可能会绕过疾病变异的一个重要组成部分，并为确定致病途径提供了一个补充机会。正是在这个相对未知的空间里，我们试图为理解ASD发病的遗传学基础做出贡献。我们建议使用“下一代”测序的最新进展来识别明显平衡的染色体重排的ASD患者中被破坏的基因。该方法还将使对小拷贝数变异的评估成为可能，这是另一个看似难以解决的遗传变异来源。然后将使用二次分子分析来确定致病机制，而不是推测原因。这些研究将从我们与大量ASD患者的合作中目前可用的丰富资源开始，这些ASD患者的核型分析确定了明显重叠的重排断裂点，并最终确定了一系列未来生物学和药理学研究的靶点。

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.