Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of enteric ganglia in a variable length of the intestine, leading to functional intestinal obstruction. The disease has an incidence of 1 in 5,000 live births and is primarily caused by mutations in the RET gene, which encodes a tyrosine kinase receptor. HSCR can be isolated or associated with other chromosomal abnormalities or congenital anomalies. Isolated HSCR exhibits complex inheritance patterns, with Mendelian modes of inheritance described, but it is generally considered a non-Mendelian malformation with low penetrance and variable expression. The RET gene plays a pivotal role in both isolated and syndromic HSCR, with epistatic interactions observed in certain syndromic cases. Other genes involved in HSCR include EDNRB, SOX10, and GDNF. The disease is genetically heterogeneous, and the identification of modifier genes is ongoing. Treatment involves surgical intervention, and the long-term prognosis is generally good, with mortality rates below 6% since the 1980s. The disease is associated with a wide range of chromosomal anomalies and congenital anomalies, including gastrointestinal malformations, craniofacial anomalies, and cardiac defects. Genetic counseling is crucial due to the high recurrence risk in families with HSCR.Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of enteric ganglia in a variable length of the intestine, leading to functional intestinal obstruction. The disease has an incidence of 1 in 5,000 live births and is primarily caused by mutations in the RET gene, which encodes a tyrosine kinase receptor. HSCR can be isolated or associated with other chromosomal abnormalities or congenital anomalies. Isolated HSCR exhibits complex inheritance patterns, with Mendelian modes of inheritance described, but it is generally considered a non-Mendelian malformation with low penetrance and variable expression. The RET gene plays a pivotal role in both isolated and syndromic HSCR, with epistatic interactions observed in certain syndromic cases. Other genes involved in HSCR include EDNRB, SOX10, and GDNF. The disease is genetically heterogeneous, and the identification of modifier genes is ongoing. Treatment involves surgical intervention, and the long-term prognosis is generally good, with mortality rates below 6% since the 1980s. The disease is associated with a wide range of chromosomal anomalies and congenital anomalies, including gastrointestinal malformations, craniofacial anomalies, and cardiac defects. Genetic counseling is crucial due to the high recurrence risk in families with HSCR.