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，在过去几十年中急剧增加。利用来自犹他州出生缺陷网络（UBDN）的数据，我们确定了1997年至2008年间出生的284名腹裂婴儿。其中，1/40（2.5%）有腹裂家族史。我们将这些病例与犹他州人口数据库（UTB）的家谱文件联系起来，建立了多代系谱。我们确定了30个多重多代“高风险”家系，其中过度聚集的家庭标准化发病率的基础上有统计学意义。这30个家系包括2 - 8个远亲受累婴儿，进一步支持了腹裂病因学的遗传贡献。犹他州大学的研究人员最近开发了一种新的方法来确定易感基因座，该方法使用基于阵列的单核苷酸多态性（SNP）数据，来自远亲受影响的个体。这一创新策略确定了多代系谱内受影响个体之间共享的基因组片段。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片段将为搜索潜在的候选区域和基因提供信息，这些区域和基因包含感兴趣的病症的关键易感性变体。一个单一的扩展的高风险谱系可以有能力识别共享段。这30个高风险家庭中的每一个都可能具有赋予腹裂易感性的不同基因（遗传异质性）。在每个基因座上，负责的等位基因在家族之间可能不同（等位基因异质性）。我们将使用这些高风险，多代家系从UB-UBDN连锁数据集调查的作用，遗传易感性在腹裂的病因。我们假设，在一个家系中，腹裂的远亲儿童具有从共同祖先遗传的遗传易感性。本提案的具体目的是：目的1）鉴定可能含有腹裂发生相关基因的基因组区域;目的2）在高通量遗传实验中评估不同生物标记物类型的可行性。这项R 03试验性研究利用了独特的资源（UB-UBDN）和犹他州大学开发的强大的新型遗传分析，以确定遗传易感性在腹裂病因学中的作用。现有的支持和现有的基础设施将在两年的时间内使项目取得成功，并将建立核心基础设施和技术专长，以支持进一步对UBDN-BRB记录链接中提供的其他出生缺陷进行遗传研究。

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.