Highly Recurrent RET Mutations and Novel Mutations in Genes of the Receptor Tyrosine Kinase and Endothelin Receptor B Pathways in Chinese Patients with Sporadic Hirschsprung Disease

摘要

Background: Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system.Methods: Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET , GDNF , EDNRB , and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls.Results: We identified 10 novel and 2 previously described mutations in RET , and 4 and 2 novel mutations in EDNRB and in EDN3 , respectively. Potential disease-causing mutations were detected in 24% of the patients. The overall mutation rate was 41% in females and 19% in males ( P = 0.06). RET mutations occurred in 19% of the patients. R114H in RET was the most prevalent mutation, representing 7% of the patients or 37% of the patients with RET mutations. To date, such a high frequency of a single mutation has never been reported in unrelated HSCR patients. Mutations in EDNRB , EDN3 , and GDNF were found in four, two, and none of the patients, respectively. Two patients with mutations in genes of the EDNRB pathway also harbored a mutation in RET . Three novel and three reported polymorphisms were found in EDNRB , EDN3 , and GDNF .Conclusion: This study identifies additional HSCR disease-causing mutations, some peculiar to the Chinese population, and represents the first comprehensive genetic analysis of sporadic HSCR disease in Chinese.