Shared genomic segments in high-risk multigenerational pedigrees with gastroschisis

Gastroschisis remains an etiologic dilemma. We posit that an underlying genetic susceptibility either separately or coupled with a periconceptional environmental exposure stimulates an inflammatory response resulting in gastroschisis. To investigate the genetic link, we applied shared genomic segment (SGS) analysis, a novel approach to discover chromosomal segments that inherit in high-risk multigenerational pedigrees.

We studied pedigrees containing distantly related children with gastroschisis originating from a common ancestor. We used the Illumina OmniExpress genotyping array with >700,000 SNPs. Samples from 40 affected children in 13 pedigrees (≥3 affected children) were genotyped to generate the high-density SNP data necessary to perform SGS analysis. Assessment of significance in SGS was determined empirically using simulations based on precise pedigree structure and modeling linkage disequilibrium (LD) for SNPs in the general population to properly account for genetic architecture. The LD model was estimated from the 1000 Genome Project using the same set of SNPs. Genome-wide significance thresholds were determined for each pedigree.

We identified six pedigrees that contained genome-wide statistically significant SGS regions inherited from a common founder. These regions were different in each pedigree, all contained immune pathway genes.

The genome-wide significant regions support a genetic susceptibility for gastroschisis. The regions are compelling candidates for regionally focused genome sequencing, enabling the discovery of coding or noncoding (e.g., regulatory) risk variants, the latter of which are unlikely to be found using conventional exomic/gene-focused approaches. This technique provides a comprehensive and focused genomic interrogation that will help to advance our understanding of gastroschisis.