Discovery of allelic variants of HOXA1 and HOXB1: Genetic susceptibility to autism spectrum disorders

Authors

  • Jennifer L. Ingram,

    1. Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
    2. Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
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  • Christopher J. Stodgell,

    1. Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
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  • Susan L. Hyman,

    1. Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
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  • Denise A. Figlewicz,

    1. Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
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  • Lowell R. Weitkamp,

    1. Department of Psychiatry, Division of Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
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  • Patricia M. Rodier

    Corresponding author
    1. Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
    • Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642
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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. Teratology 62:393–405, 2000. © 2000 Wiley-Liss, Inc.

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