Authors
Benthal, J. T., Avila, J. A., Smith, J. R., Southard-Smith, E. M.
Abstract
Background Hirschsprung disease (HSCR) is characterized by absence of enteric ganglia (aganglionosis) along variable lengths of the distal intestine. This disorder results from deficient colonization of fetal intestine by enteric neural crest-derived cells (ENCDCs). HSCR exhibits complex, multifactorial inheritance with penetrance and severity varying widely even within a family. SOX10 is among causal genes that predispose to aganglionosis. Yet, how gene interactions influence severity of HSCR aganglionosis is not understood. We previously used an F1-intercross strategy to map genetic modifiers of aganglionosis in the Sox10Dom HSCR mouse. Here we employ an extended pedigree mapping approach and complementary omics analyses of the developing Enteric Nervous System (ENS) to identify modifier loci that affect severity of HSCR aganglionosis. Results To identify loci that modify aganglionosis extent we undertook genome-wide association study (GWAS) of an extended pedigree of Sox10Dom mice on a mixed C57BL/6J x C3HeBFeJLe-a/a background. GWAS uncovered genetic modifiers of aganglionosis severity in this cohort. Within each modifier interval, we prioritize candidate genes based on gene expression in the developing ENS, proximity to open chromatin regions in ENCDCs, and presence of conserved SOX10 binding motifs. This strategy identified known genes in ENS development as well as multiple novel genes. Dach1 emerged as a top priority gene for modifying ENCDCs migration and thus influencing aganglionosis severity. Conclusions This study identifies genome intervals and intrinsic genes that modify Sox10Dom aganglionosis severity and that are candidate modifiers of human HSCR severity.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Nov 2025.
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