Unraveling the molecular basis of clinical heterogeneity in Hirschsprung disease through gene expression analysis.

To assess the association of RET, NRG1, SEMA3, and RARB gene variants with clinical phenotypes of Hirschsprung disease (HSCR) in a population with limited genetic data (Aceh, Indonesia). This study employed an observational analytical design with a cross-sectional approach. A total of 57 patients who underwent HSCR surgery were included. Demographic, clinical, and histopathological data were collected. Both a-ganglionic and ganglionic tissues from the colon or rectum were sampled from HSCR patients, along with control samples from each patient with anorectal malformation. mRNA expression of RET, NRG1, SEMA3, and RARB genes was measured using real-time PCR. Among the 57 patients, most were male (70.2%) and had short-segment HSCR (98.2%). NRG1 expression was significantly reduced in aganglionic colon tissue compared with controls (2.84-fold; p = 0.02). RET expression was markedly decreased in both aganglionic (3.23-fold; p = 0.02) and ganglionic tissues (3.89-fold; p = 0.02). Similarly, SEMA3 expression was significantly lower in aganglionic (3.05-fold; p = 0.03) and ganglionic tissues (2.94-fold; p = 0.04) relative to control colon. Reduced expression of NRG1, RET, and SEMA3 was observed in HSCR colon tissues, suggesting their involvement in disease pathogenesis among Acehnese patients.