Shared Genomic Segments in Multiplex Families with Gastroschisis

描述（由申请人提供）：腹裂是一种严重的出生缺陷，婴儿出生时腹部器官在体外，这种情况在过去几十年里急剧增加。使用犹他州出生缺陷网络（UBDN）的数据，这是一个全国性的、以人口为基础的出生缺陷监测系统，我们确定了1997年至2008年间出生的284名胃裂婴儿。其中，40人中有1人（2.5%）有胃裂家族史。我们将这些病例与犹他州人口数据库（UPDB）的家谱文件联系起来，并创建了多代谱系。我们确定了30个多重多代“高风险”谱系，在这些谱系中，基于家族标准化发病率，过度聚类具有统计学意义。这30个谱系包括2到8个有远亲关系的受影响婴儿，进一步支持遗传对胃裂病病因的贡献。犹他大学的研究人员最近开发了一种新的方法来识别易感位点，该方法使用基于阵列的单核苷酸多态性（SNP）数据，这些数据来自远亲受影响个体。这一创新策略确定了多代谱系中受影响个体共享的基因组片段。随着减数分裂距离的增加，预期的DNA共享变得越来越不可能。鉴定来自共同祖先的超过预期的共享DNA片段将为寻找潜在的候选区域和基因提供信息，这些区域和基因包含对感兴趣的条件的关键易感性变异。单个扩展的高风险谱系可以识别共享片段。这30个高危家庭中的每一个都可能有不同的基因，从而导致胃裂易感性（遗传异质性）。在每个位点上，负责的等位基因在不同的家族之间可能不同（等位基因异质性）。我们将使用来自UPDB-UBDN关联数据集的这些高风险、多代谱系来研究遗传易感性在胃裂病因学中的作用。我们假设远亲儿童与胃裂在一个谱系共享遗传易感性，已从一个共同的祖先遗传。本提案的具体目标是：目标1)确定可能包含胃裂发育相关基因的基因组区域；目的2)评估不同生物标本类型在高通量遗传实验中的生存能力。这项R03先导研究利用犹他大学开发的独特资源（UPDB-UBDN）和强大的新型遗传分析来确定遗传易感性在胃裂病因学中的作用。现有的支助和现有的基础设施将使项目在两年时间框架内取得成功，并将建立核心基础设施和技术专门知识，以支持从udn - updb记录联系中获得的其他出生缺陷的进一步遗传研究。

DESCRIPTION (provided by applicant): Gastroschisis is a serious birth defect where babies are born with their abdominal organs outside of their body which has dramatically increased over the past several decades. Using data from the Utah Birth Defect Network (UBDN), a statewide, population-based birth defect surveillance system, we identified 284 infants with gastroschisis born between 1997 and 2008. Among these, 1 in 40 (2.5%) had a family history of gastroschisis. We linked these cases to the genealogic files of the Utah Population Database (UPDB) and created multigenerational pedigrees. We identified 30 multiplex multigenerational 'high-risk' pedigrees, in whom the excessive clustering was statistically significant based on the familial standardized incidence ratio. The 30 pedigrees included between two and eight distantly-related affected infants, further supporting a genetic contribution to the etiology of gastroschisis. University of Utah investigators recently developed a novel approach to identify susceptibility loci that uses array-based single nucleotide polymorphism (SNP) data from distantly related affected individuals. This innovative strategy identifies genomic segments shared across affected individuals within multigenerational pedigrees. The expected DNA sharing becomes increasingly unlikely with increased meiotic distance. Identification of shared DNA segments from a common ancestor in excess of that expected will inform the search for potential candidate regions and genes that contain critical susceptibility variants for the condition of interest. A single extended high-risk pedigree can have the power to identify shared segments. Each of these 30 high-risk families may have a different gene(s) that confers gastroschisis susceptibility (genetic heterogeneity). At each locus, the responsible allele(s) may vary between families (allelic heterogeneity). We will investigate the role of a genetic susceptibility in the etiology of gastroschisis using these high-risk, multigenerational pedigrees from the UPDB-UBDN linked dataset. We hypothesize that distantly related children with gastroschisis within a pedigree share a genetic susceptibility that has been inherited from a common ancestor. The Specific Aims of this proposal are: Aim 1) Identify genomic regions likely to harbor genes involved in the development of gastroschisis; and Aim 2) Assess viability of different biospecimen-types in high-throughput genetic experiments. This R03 pilot study leverages unique resources (UPDB-UBDN) and powerful novel genetic analyses developed at the University of Utah to identify the contribution of genetic susceptibility in the etiology of gastroschisis. The available support and existing infrastructures will result in a successful project within the two year time frame and will establish the core infrastructure and technical expertise to support further genetic studies for other birth defects available from the UBDN-UPDB record-linkage.