Shared genomic segments in high-risk multigenerational pedigrees with gastroschisis

Area of Science:

• Genetics
• Developmental Biology
• Pediatrics

Background:

• Gastroschisis etiology remains unclear, with hypotheses involving genetic susceptibility and environmental factors.
• A genetic predisposition, potentially interacting with periconceptional exposures, is proposed to trigger an inflammatory response leading to gastroschisis.
• Novel genomic analysis methods are needed to investigate the genetic underpinnings of gastroschisis.

Purpose of the Study:

• To investigate the genetic link in gastroschisis using shared genomic segment (SGS) analysis.
• To identify chromosomal segments inherited in high-risk multigenerational pedigrees affected by gastroschisis.
• To explore the potential role of genetic susceptibility in gastroschisis etiology.

Main Methods:

• Studied 13 multigenerational pedigrees with at least three affected children each.
• Genotyped 40 affected children using the Illumina OmniExpress array (>700,000 SNPs).
• Applied SGS analysis, empirically assessing significance through simulations and linkage disequilibrium (LD) modeling from the 1000 Genomes Project.

Main Results:

• Identified genome-wide statistically significant SGS regions in six pedigrees, all inherited from a common founder.
• These significant regions varied across pedigrees but consistently contained immune pathway genes.
• The findings provide empirical evidence for shared genomic segments associated with gastroschisis.

Conclusions:

• The identified genome-wide significant regions support a genetic susceptibility for gastroschisis.
• These regions are prime candidates for targeted genome sequencing to discover novel risk variants, including noncoding regulatory elements.
• This focused genomic approach advances the understanding of gastroschisis pathogenesis.