Genetic analysis of 15q11-q13 in Autism

描述（由申请人提供）：自闭症是一种神经精神障碍，表现出复杂的遗传病因，具有显著的临床和基因座异质性。影响染色体15 q11-q13的重复是自闭症中最常见的细胞遗传学异常，连锁和关联研究表明，该区域与染色体正常家庭中自闭症的遗传易感性有关。我们建议通过（1）采用365个亲子三人组和330个多元家庭的彻底表型数据集;（2）表征双链子介导的重排和潜在的表观遗传效应;（3）鉴定遗传上更同质的亚组，以检测和表征遗传效应;（4）研究与15 q11-q13相关的自闭症遗传风险的遗传基础。和（4）使用单核苷酸多态性（SNP）进行高分辨率连锁不平衡作图，以确定用于分析这些家族中等位基因效应的单倍型。我们的目标将通过五个具体目标来实现。(1)使用标准化的诊断工具和算法对单胎家庭进行招募和详细的临床评估。(2)涉及15 q的染色体重排的表征和印迹表达的潜在表观遗传失调的检查。(3)构建15 q11-q13候选区域的完整单倍型图谱，并鉴定用于区分所有常见（>5%）单倍型的简化SNP集。(4)个体标记和多标记单倍型在自闭症家系等位基因和上位效应研究中的应用。(5)孤独症15 q11-q13等位基因变异的鉴定及这些变异的功能效应的初步表征将筛选候选基因内的相关单倍型区块和/或功能显著区域以鉴定可能的功能变体。我们将通过与其他小组合作检查独立数据集来评估任何遗传发现的意义。这些努力的结果将是了解15 q11-q13如何有助于自闭症和更广泛的自闭症谱系的遗传易感性。

DESCRIPTION (provided by applicant): Autism is a neuropsychiatric disorder exhibiting a complex genetic etiology with significant clinical and locus heterogeneity. Duplications affecting chromosome 15q11-q13 are the most common cytogenetic abnormality in autism, and linkage and association studies indicate that this region is involved in inherited susceptibility for autism in chromosomally normal families. We propose dissecting the genetic basis for inherited risk associated with 15q11-q13 in autism by (1) employing a thoroughly phenotyped dataset of 365 parent-child trios and 330 multiplex families; (2) characterization of duplicon-mediated rearrangements and potential epigenetic effects; (3) identifying genetically more homogeneous subgroups with which to detect and characterize genetic effects; and (4) performing high-resolution linkage disequilibrium mapping using single nucleotide polymorphisms (SNPs) to define haplotypes for use in analysis of allelic effects in these families. Our goal will be accomplished through five specific aims. (1) Recruitment and detailed clinical assessment of singleton families using a standardized panel of diagnostic instruments and algorithms. (2) Characterization of chromosomal rearrangements involving 15q and examination of potential epigenetic dysregulation of imprinted expression. (3) Construction of a complete haplotype map for the 15q11-q13 candidate region and identification of a reduced set of SNPs for discrimination of all common (>5%) haplotypes. (4) Application of individual markers and multi-marker haplotypes to characterize allelic and epistatic effects in these autism families. (5) Identification of 15q11-q13 allelic variants in autism and preliminary characterization of the functional effect of those variations. Associated haplotype blocks and/or functionally-significant regions within candidate genes will be screened to identify likely functional variants. We will evaluate the significance of any genetic findings by examination of independent datasets through collaboration with other groups. The result of these efforts will be an understanding of how 15q11-q13 contributes to inherited susceptibility in autism and the broader autism spectrum.