RARE VARIANT GENETICS, CONTACTIN-RELATED PROTEINS AND AUTISM

罕见变异遗传学、接触素相关蛋白和自闭症

• 批准号: 7808784
• 负责人: MATTHEW STATE
• 金额: $ 33.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7808784
• 关键词: Adhesions; Affect; Agreement; Alleles; Amish; Architecture; Autistic Disorder; Axon; Bioinformatics; Brain; Cell Adhesion; Child; Chromosomal Rearrangement; Chromosome Structures; Chromosome abnormality; Chromosomes; Code; Complex; Control Groups; Copy Number Polymorphism; Cytogenetics; Data; Development; Developmental Delay Disorders; Disease; Early Diagnosis; Eating; Family; Frequencies; Functional disorder; Gene Family; Genes; Genetic; Genetic Polymorphism; Genomics; Grant; Haplotypes; Individual; Investigation; Laboratories; Language Delays; Letters; Light; Mental Retardation; Methods; Microscopic; Missense Mutation; Molecular Cytogenetics; Muscle fasciculation; Mutation; Mutation Analysis; Neurons; Panthera leo; Patient observation; Patients; Phenotype; Play; Polymorphism Analysis; Population; Protein Family; Proteins; Rare Diseases; Recruitment Activity; Reporting; Research; Risk; Role; Sampling; Screening procedure; Seizures; Syndrome; Tertiary Protein Structure; Transcript; Variant; Work; X Chromosome; autism spectrum disorder; axon growth; base; boys; chromosome 3p deletion syndrome; chromosome 3p duplication syndrome; contactin; disability; disorder risk; experience; founder mutation; gene discovery; genetic linkage analysis; genetic variant; insight; interest; migration; molecular array; myelination; neuropsychiatry; novel strategies; protein function; repository; social; statistics

There is ample evidence that rare genetic variants may contribute to a small subset of individuals presenting with Autism Spectrum Disorders (ASDs). The characterization of these unusual cases may provide important insights into pathophysiological mechanisms underlying disease. Our laboratory has leveraged the comprehensive phenotyping capabilities of the Yale Autism Research Group to focus on the discovery of rare variants contributing to developmental and social disability. Recently we have studied three unrelated patients with ASD and/or Mental Retardation (MR) and chromosomal abnormalities, all of who were found to have disruptions of genes in the Contactin (CNTN) or Contactin Association Protein (CNTNAP) families, including CNTN4, CNTNAP2 and CNTNAP4. These neuronal adhesion and recognition molecules are known to play key roles in axon pathfinding, fasciculation and neuronal-glial interactions. We have undertaken extensive re-sequencing efforts and, in our initial analysis of Contactin Associated Protein, we have identified a statistically significant increase in the burden of potentially damaging missense mutations among 218 cases and 449 controls regardless of whether we consider all non-synonymous variants or only those predicted by bioinformatics approaches to be deleterious to protein function. This data is particularly compelling in light of two additional findings: a rare recessive mutation in this gene found in association with seizures, developmental delay and autistic features in Amish families; and, unpublished data from collaborators at UCLA showing a common haplotype of CNTNAP2 associated with language delay in individuals with Autism. Based on our recent findings we now propose to: 1) replicate the mutation burden analysis in CNTNAP2 and perform a similar preliminary study in patients with developmental delay but not social disability; 2) perform initial and, if warranted, replication studies of the other molecules disrupted by chromosomal abnormalities, Contactin 4 and Contactin Associated Protein 4\ and 3) continue our gene discovery efforts using both conventional and array based cytogenetics on the well-characterized patients recruited under Projects 1-IV of this application focusing on the identification of rare, deleterious changes in chromosome structure.

有足够的证据表明罕见的遗传变异可能有助于一小部分个体 呈现自闭症谱系障碍（ASD）。这些异常情况的表征可能 提供有关疾病潜在的病理生理机制的重要见解。我们的实验室有 利用耶鲁自闭症研究小组的全面表型能力来关注 发现有助于发展和社会残疾的稀有变体。最近我们研究了三个 无关的ASD和/或智力低下（MR）和染色体异常的患者，所有谁 发现在接触蛋白（CNTN）或接触蛋白关联蛋白中具有基因破坏 （CNTNAP）包括CNTN4，CNTNAP2和CNTNAP4在内的家庭。这些神经元的粘附和识别 已知分子在轴突探路，迷恋和神经元相互作用中起关键作用。我们 已经采取了广泛的重新努力，在我们对接触蛋白相关蛋白的初步分析中， 我们已经确定了潜在损害错义的负担统计学上的显着增加 不管我们是否考虑所有非同义词 变体或仅通过生物信息学预测的变体对蛋白质功能有害。这个数据 鉴于两个其他发现，特别令人信服：在此基因中发现的一种罕见隐性突变 与癫痫发作，发育延迟和自闭症特征相关联；而且，未出版 来自UCLA合作者的数据显示了与语言延迟相关的CNTNAP2的常见单倍型 在自闭症患者中。根据我们最近的发现，我们现在建议：1）复制突变负担 在CNTNAP2中分析并在发育延迟的患者中进行类似的初步研究 社会残疾； 2）执行初始的，如果有必要，则对其他分子的复制研究被破坏 染色体异常，接触蛋白4和接触蛋白相关蛋白4 \和3）继续我们的基因 使用常规和阵列的细胞遗传学对特征良好的患者的发现工作 根据本申请的1-IV项目招募，重点是识别罕见，有害变化的变化 染色体结构。