WOFAPS 2025 8th World Congress of Pediatric Surgery

Avriana Pety Wardani, Dito Anurogo

Hospital RSUP Dr Kariadi Semarang

Immunogenetic Architecture of Hirschsprung Disease: RET Variants, Molecular Crosstalk, and Polygenic Interactions in Enteric Neurocristopathies

Avriana Pety Wardani¹, Dito Anurogo^2,3*

¹ Kariadi Hospital, Semarang, Indonesia

² Faculty of Health and Medical Sciences, Universitas Muhammadiyah Makassar, Indonesia

³ Institut Molekul Indonesia

*Corresponding email: avrianagarg@gmail.com. dito.anurogo@med.unismuh.a.id

Abstract

Hirschsprung disease (HSCR), a neurocristopathy affecting 1 in 5,000 live births, is primarily characterized by distal intestinal aganglionosis resulting from the aberrant migration, proliferation, or differentiation of neural crest-derived enteric progenitors. The most extensively studied genetic determinant, the RET proto-oncogene, encodes a receptor tyrosine kinase essential for enteric nervous system (ENS) ontogeny. Yet, germline RET mutations are observed in only 7–35% of cases, predominantly in long-segment and familial HSCR, and frequently in the context of syndromic presentations such as MEN2A (Multiple Endocrine Neoplasia type 2A), implicating complex immunogenetic mechanisms beyond monogenic inheritance. Recent integrative multi-omics analyses, including transcriptomic, miRNAomic, and network-based interactome modeling, have elucidated that HSCR exhibits a polygenic and multifactorial etiology involving a constellation of at least 13 genes (RET, EDNRB, EDN3, GDNF, SOX10, ECE1, NTN, ZEB2, PHOX2B, L1CAM, KIAA1279, TCF4, and NRG1). These loci encode proteins that orchestrate key signaling pathways regulating immune-molecular crosstalk, neurogenic inflammation, and neuroepithelial development. Intriguingly, rare and common polymorphisms in RET exons, including synonymous variants affecting mRNA splicing (e.g., exon 11), act synergistically with non-coding RNAs (miRNAs, lncRNAs, and circRNAs) to modulate expression thresholds critical for neural crest cell fate decisions. Moreover, immunogenetic profiling suggests that dysregulated RET signaling compromises epithelial barrier function and gut-immune homeostasis, potentiating Hirschsprung-associated enterocolitis (HAEC), the leading cause of mortality in HSCR. The RET "Janus" paradox—exemplified by its dual role in HSCR and MEN2A via context-specific gain- and loss-of-function mutations—further underscores the immunogenomic intricacy and dynamic epistasis underlying this disorder. Emerging bioengineering approaches, including enteric neural stem cell (ENSC) transplantation and human pluripotent stem cell (hPSC)-derived ENS progenitor grafts, offer promising avenues for regenerative immunomodulation.

This synthesis delineates HSCR as an archetype of immunogenetically-driven congenital disease, advocating for precision molecular diagnostics integrating RET-centered genotyping, epigenetic profiling, and immune-network interrogation. Such a systems immunogenetics paradigm will catalyze novel diagnostic, prognostic, and therapeutic strategies, shifting HSCR management from surgical palliation toward biologically informed intervention.

Keywords: Hirschsprung disease, RET proto-oncogene, immunogenetics, enteric nervous system, neural crest cells, enterocolitis, polygenic inheritance, non-coding RNA, regenerative medicine.

Graphical abstract is created with support of AI.