Abstract
Males are at least four times more likely to develop autism than females. Among relatives with a broader autistic phenotype, males predominate too. Autism is a highly heritable disorder, yet genome scans have not revealed any predisposing loci on the sex chromosomes. A nongenetic explanation for male vulnerability, such as exposure to prenatal androgens, is unlikely for a variety of reasons. A novel genetic mechanism that resolves many of the outstanding difficulties is outlined here. The imprinted-X liability threshold model hypothesizes that the threshold for phenotypic expression of many autistic characteristics is influenced by an imprinted X-linked gene(s) that is protective in nature. Imprinted genes are known to play an important role in normal fetal and behavioral development. The gene is expressed only on the X-chromosome that is inherited from the father and raises the threshold for phenotypic expression. It is normally silenced when transmitted maternally. Because only females have a paternal X-chromosome, the threshold for phenotypic expression is higher in them than in males. Evidence for the existence of the genetic locus was found in a study of females with X-monosomy (Turner's syndrome) in which females had either a single paternal or maternal X-chromosome. Identifying the sites of action of this X-linked gene could lead to the discovery of autosomal loci that confer more directly a predisposition to autism.
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Abbreviations
- WT1:
-
Wilms' tumor 1
- HTR2A:
-
serotonin-2A (5-HT2A) receptor
- PDD:
-
pervasive developmental disorder
- HFA:
-
high-functioning autism
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Acknowledgements
The genetic analyses of Turner's syndrome were done in collaboration with the Wessex Regional Genetics Laboratory at Salisbury District Hospital and were directed by Patricia Jacobs. Neuropsychologic testing was done in collaboration with Dorothy Bishop at the Department of Experimental Psychology in Oxford. Validation of the Social Communication Checklist was conducted by Jonna Kuntsi with assistance from Jim Stevenson. Other contributions were made by Kate Elgar, Elena Morris, Joanne Coldwell, Elinore Percy, Sarah Cave, Anne O'Herlihy, Rikki South, Jennifer Smith, Monica Power, Gina Aamodt-Leeper, Monique Bacarese-Hamilton, Catharine Creswell, Rhona McGurk, Brian Coppin, and David Robinson. Marcus Pembrey provided many valuable insights. We thank all those pediatric consultants who assisted with the recruitment of patients and the schools that participated. Finally, we thank especially all the subjects of our investigation and their families for the time they generously gave to us.
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Supported by the Wellcome Trust and the Child Growth Foundation. Compilation of the national register of Turner syndrome was supported by the British Society for Paediatric Endocrinology and by Pharmacia Ltd.
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Skuse, D. Imprinting, the X-Chromosome, and the Male Brain: Explaining Sex Differences in the Liability to Autism. Pediatr Res 47, 9 (2000). https://doi.org/10.1203/00006450-200001000-00006
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DOI: https://doi.org/10.1203/00006450-200001000-00006
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