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Analysis of X chromosome inactivation in autism spectrum disorders

Gong, Ziaohong; Bacchelli, Elena; Blasi, Francesca; Toma, Claudio; Betancur, Catalina; Chaste, Pauline; Delorme, Richard; Durand, Christelle M; Fauchereau, Fabien and Goubran Botros, Hany, et al. (2008) In American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 147B(6). p.830-835
Abstract
Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and... (More)
Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes. (Less)
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published
subject
keywords
autistic disorder skewed X-inactivation, linkage study, X-linked mutation
in
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
volume
147B
issue
6
pages
830 - 835
publisher
International Society of Psychiatric Genetics
external identifiers
  • scopus:51449112549
ISSN
1552-4841
DOI
10.1002/ajmg.b.30688
language
English
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no
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38aa1136-b46d-4c0d-a1b8-1484d0710ff4 (old id 1439947)
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2009-07-31 15:45:58
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2017-09-10 03:41:36
@article{38aa1136-b46d-4c0d-a1b8-1484d0710ff4,
  abstract     = {Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes.},
  author       = {Gong, Ziaohong and Bacchelli, Elena and Blasi, Francesca and Toma, Claudio and Betancur, Catalina and Chaste, Pauline and Delorme, Richard and Durand, Christelle M and Fauchereau, Fabien and Goubran Botros, Hany and Leboyer, Marion and Mouren-Simeoni, Marie-Christine and Nygren, Gudrun and Anckarsäter, Henrik and Råstam, Maria and Gillberg, Carina and Gillberg, Christopher and Moreno-De-Luca, Daniel and Carone, Simona and Nummela, Ilona and Rossi, Mari and Battaglia, Agatino and (MGSAC), The International Molecular Genetic Study of Autism Consortium and Jarvela, Irma and Maestrini, Elena and Bourgeron, Thomas},
  issn         = {1552-4841},
  keyword      = {autistic disorder skewed X-inactivation,linkage study,X-linked mutation},
  language     = {eng},
  number       = {6},
  pages        = {830--835},
  publisher    = {International Society of Psychiatric Genetics},
  series       = {American Journal of Medical Genetics Part B: Neuropsychiatric Genetics},
  title        = {Analysis of X chromosome inactivation in autism spectrum disorders},
  url          = {http://dx.doi.org/10.1002/ajmg.b.30688},
  volume       = {147B},
  year         = {2008},
}