Genes disrupted by balanced genomic rearrangements in autism spectrum disorders

描述（由申请人提供）：广泛性发育障碍的一个强有力的遗传贡献被广泛接受，但遗传性的相当大一部分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有两条不同的道路。第一个已经使用全基因组关联范例评估了常见变异。这种设计在异质性疾病模型（如炎症性肠病和II型糖尿病）方面取得了进展，但在确定复杂神经精神疾病（如精神分裂症）的风险位点方面不太成功。第二种是利用先进的技术提出常见病的罕见变异假说。在最近的研究中，导致遗传物质净获得或损失的结构变异与几种神经精神表型相关，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）的遗传风险的一部分可归因于这些基因组事件，并且许多正在进行的常见多态性和罕见异常研究的高潮可能会为ASD的遗传风险提供重要的见解。两种方法都没有明确解决的是平衡染色体重排带来的机会。ASD患者中此类事件发生率的估计值大幅增加，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绕过疾病变异的重要组成部分和确定致病途径的补充机会，特别是如果它针对与常见多态性或剂量变异不同的遗传贡献。正是在这个相对未开发的空间，我们寻求有助于理解ASD发病机制的遗传基础。我们建议使用“下一代”测序的最新进展，以确定在ASD患者明显平衡的染色体重排的基因中断。这些方法将建立在癌症遗传学的创新基础上，定制它们用于分析异常生殖细胞核型。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描述的基因组变异的另一个模糊来源。该提案还将通过进行二次分子分析来确定疾病易感性的致病机制，而不是仅从从头状态或患者和对照队列中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分开。这些研究将开始与丰富的资源，目前可在我们的合作，大量的ASD患者与易位确定的核型分析，并最终在表征一系列未来的生物学和药理学研究的目标。 公共卫生相关性：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性和罕见的结构变异。目前的方法没有明确解决的是平衡染色体重排带来的机会。与一般人群相比，ASD患者中此类事件发生率的估计值大幅增加，但其影响在很大程度上是未知的，因为目前的方法无法快速准确地检测这些基因组事件。未能适当考虑ASD患者的这一亚组可能绕过疾病变异的重要组成部分和确定致病途径的补充机会。正是在这个相对未开发的空间，我们寻求有助于理解ASD发病机制的遗传基础。我们建议使用“下一代”测序的最新进展，以确定在ASD患者明显平衡的染色体重排的基因中断。该方法还将能够评估小拷贝数变异，这是另一个看似棘手的遗传变异来源。然后将使用二级分子分析来确定致病机制，而不是推测因果关系。这些研究将开始与丰富的资源，目前可在我们的合作，一个显着的ASD患者与明显重叠的重排断点确定的核型分析，并最终在表征一系列未来的生物学和药理学研究的目标。

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.