title: Clinical and genetic correlations of familial Hirschsprung's disease.
abstract: BACKGROUND
  The risk of familial transmission in Hirschsprung's disease (HSCR) currently lacks correlation between the clinical phenotype and the underlying genetic factors. The aim of this study was to clinically evaluate familial HSCR transmission and to correlate with the genetic background.
  
  
  METHODS
  Clinical and gene analysis of familial HSCR patients were explored. DNA from 45 patients (35 kindreds) was screened for genetic variations of the RET, and EDNRB genes were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to controls.
  
  
  RESULTS
  Male:female ratio (3:1) had a female proband in 4 families. Aganglionosis was significantly more frequent with total colonic aganglionosis (TCA) in 40% familial cases (viz: 17/43 (43%) vs. 19/342 non-familial patients (5.6%) (p<0.01)). Transmission of S-HSCR was observed in 13 (31%), which was associated with EDNRB variation. RET gene promoter variation correlated with extended aganglionosis in 6/35 kindreds (17%). In 3 kindreds, both significant EDNRB and RET mutations were identified and where present were associated with increased penetrance in succeeding generations. An increased penetrance with succeeding generations occurred in 6 (14%). In a further 3 generation family, extensive variations in exon 6, 13, and 18 affected 3 males with progressive penetration and aganglionic length, including total intestinal aganglionosis in the further offspring. RET and MEN association was noted in 5 kindreds (14.3%) related to RET variations at Cysteine sites.
  
  
  CONCLUSIONS
  Cumulative effects of the RET and EDNRB genes contribute to long-segment and total colonic aganglionosis.
authors: Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, Western Cape, South Africa. Electronic address: swm@sun.ac.za.
authors: Sam W
authors: SW
authors: Moore
authors: Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, Western Cape, South Africa.
authors: Monique
authors: M
authors: Zaahl
mesh_terms: D002648:Child; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D044023:Receptor, Endothelin B / Q000235:genetics*
chemical_list: C000588596:EDNRB protein, human; D044023:Receptor, Endothelin B; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: EDNRB gene; Familial; Genetic RET protooncogene; Hirschsprung’s disease