Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of ganglion cells in the enteric nervous system, leading to functional intestinal obstruction. It is the most common genetic cause of this condition, with an incidence of 1/5000 live births. HSCR is a neurocristopathy, arising from the failure of neural crest cell migration during fetal development. It can occur as an isolated condition or in association with other syndromes. The major susceptibility gene is RET, which is also involved in multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC). Mutations in RET account for about 50% of familial and 15% of sporadic cases. Other genes, such as EDNRB and GDNF, are also implicated. HSCR is genetically heterogeneous, with 10 genes and five loci involved. It is associated with a variety of syndromes, including Waardenburg syndrome, neuroblastoma, and Mowat-Wilson syndrome. The disease has a sex-dependent penetrance, with higher prevalence in males. Genetic counseling is important due to the high recurrence risk (relative risk of 200). Surgical treatment is the mainstay, with various procedures available. HSCR is a complex condition with multiple genetic and environmental factors contributing to its development. The identification of modifier genes and understanding of genetic interactions are ongoing areas of research.Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of ganglion cells in the enteric nervous system, leading to functional intestinal obstruction. It is the most common genetic cause of this condition, with an incidence of 1/5000 live births. HSCR is a neurocristopathy, arising from the failure of neural crest cell migration during fetal development. It can occur as an isolated condition or in association with other syndromes. The major susceptibility gene is RET, which is also involved in multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC). Mutations in RET account for about 50% of familial and 15% of sporadic cases. Other genes, such as EDNRB and GDNF, are also implicated. HSCR is genetically heterogeneous, with 10 genes and five loci involved. It is associated with a variety of syndromes, including Waardenburg syndrome, neuroblastoma, and Mowat-Wilson syndrome. The disease has a sex-dependent penetrance, with higher prevalence in males. Genetic counseling is important due to the high recurrence risk (relative risk of 200). Surgical treatment is the mainstay, with various procedures available. HSCR is a complex condition with multiple genetic and environmental factors contributing to its development. The identification of modifier genes and understanding of genetic interactions are ongoing areas of research.