title: Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders.
abstract: BACKGROUND
  Family studies have demonstrated that the autism spectrum disorders (ASDs) have a major genetic etiologic component, but expression and penetrance of the phenotype are variable. Mice with null mutations of Hoxa1 or Hoxb1, two genes critical to hindbrain development, have phenotypic features frequently observed in autism, but no naturally occurring variants of either gene have been identified in mammals.
  
  
  METHODS
  By sequencing regions of genomic DNA of patients with autism spectrum disorders, we detected a substitution variant at HOXA1 and an insertion variant at HOXB1, both in coding regions of the genes. Fifty-seven individuals ascertained for a diagnosis of an ASD, along with 166 of their relatives, were typed for these variants. Two non-ASD populations were typed, and the frequency of the newly identified alleles was determined in all groups. The genotypes of the ASD families were tested for conformation to Hardy-Weinberg proportions and Mendelian expectations for gene transmission.
  
  
  RESULTS
  The frequency of the variants was 10-25% in persons of European or African origin. In the ASD families, there was a significant deviation from the HOXA1 genotype ratios expected from Hardy-Weinberg proportions (P = 0.005). Among affected offspring, a significant deviation from Mendelian expectation in gene transmission (P = 0.011) was observed. No statistically significant effects were detected when the same analyses were applied to the HOXB1 locus, but there was evidence of an interaction between HOXA1, HOXB1, and gender in susceptibility to ASDs.
  
  
  CONCLUSIONS
  The results support a role for HOXA1 in susceptibility to autism, and add to the existing body of evidence implicating early brain stem injury in the etiology of ASDs.
authors.affiliation: Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Ingram
authors.forename: C J
authors.initials: CJ
authors.lastname: Stodgell
authors.forename: S L
authors.initials: SL
authors.lastname: Hyman
authors.forename: D A
authors.initials: DA
authors.lastname: Figlewicz
authors.forename: L R
authors.initials: LR
authors.lastname: Weitkamp
authors.forename: P M
authors.initials: PM
authors.lastname: Rodier
mesh_terms: D000015:Abnormalities, Multiple / Q000453:epidemiology; D000483:Alleles; D020817:Asperger Syndrome / Q000453:epidemiology / Q000235:genetics; D001321:Autistic Disorder / Q000453:epidemiology / Q000235:genetics*; D001933:Brain Stem / Q000196:embryology; D015897:Comorbidity; D004252:DNA Mutational Analysis; D005314:Embryonic and Fetal Development / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005801:Genes, Homeobox; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology; D008297:Male; D009518:New York / Q000453:epidemiology; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C101121:HOXB1 homeodomain protein