Highlights
A large multi-platform study of sporadic Hirschsprung disease (HSCR) identified a predominant molecular subgroup, affecting 79.6% of patients, characterized by coordinated repression of neurogenesis-related transcriptional programs.
PRDM9 emerged as a mechanistic candidate: it was downregulated in aganglionic colon, showed promoter hypermethylation, and its perturbation in zebrafish, mice, and human induced pluripotent stem cell-derived enteric neural crest cells (ENCCs) impaired enteric neuronal differentiation and gut motility.
