title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong SAR, China.
authors.forename: Mercè
authors.initials: M
authors.lastname: Garcia-Barceló
authors.forename: Mai-Har
authors.initials: MH
authors.lastname: Sham
authors.forename: Wing-Shan
authors.initials: WS
authors.lastname: Lee
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Benedict Ling-Sze
authors.initials: BL
authors.lastname: Chen
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Joyce Suet-Wan
authors.initials: JS
authors.lastname: Wong
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
mesh_terms: D044466:Asian People / Q000235:genetics; D002681:China; D019334:Endothelin-3 / Q000378:metabolism; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017466:Receptors, Endothelin / Q000235:genetics*; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D019334:Endothelin-3; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D017466:Receptors, Endothelin; C098996:endothelin-3 receptor; D020794:Receptor Protein-Tyrosine Kinases