title: Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events.
abstract: BACKGROUND
  RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In the present study, we have performed a comprehensive study of our HSCR series evaluating the involvement of both RET rare variants (RVs) and common variants (CVs) in the context of the disease.
  
  
  METHODS
  RET mutational screening was performed by dHPLC and direct sequencing for the identification of RVs. In addition Taqman technology was applied for the genotyping of 3 RET CVs previously associated to HSCR, including a variant lying in an enhancer domain within RET intron 1 (rs2435357). Statistical analyses were performed using the SPSS v.17.0 to analyze the distribution of the variants.
  
  
  RESULTS
  Our results confirm the strongest association to HSCR for the "enhancer" variant, and demonstrate a significantly higher impact of it in male versus female patients. Integration of the RET RVs and CVs analysis showed that in 91.66% of cases with both kinds of mutational events, the enhancer allele is in trans with the allele bearing the RET RV.
  
  
  CONCLUSIONS
  A gender effect exists on both the transmission and distribution of rare coding and common HSCR causing mutations. In addition, these RET CVs and RVs seem to act in a synergistic way leading to HSCR phenotype.
authors: Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors: Rocio
authors: R
authors: Núñez-Torres
authors: Raquel M
authors: RM
authors: Fernández
authors: Manuel Jesus
authors: MJ
authors: Acosta
authors: Maria Del Valle
authors: Mdel V
authors: Enguix-Riego
authors: Martina
authors: M
authors: Marbá
authors: Juan
authors: J
authors: Carlos de Agustín
authors: Luis
authors: L
authors: Castaño
authors: Guillermo
authors: G
authors: Antiñolo
authors: Salud
authors: S
authors: Borrego
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004742:Enhancer Elements, Genetic; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005816:Genetic Complementation Test; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012727:Sex Characteristics; D013030:Spain
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human