Shared Genomic Segments in Multiplex Families with Gastroschisis

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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.