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

Ingram, Jennifer L.; Stodgell, Christopher J.; Hyman, Susan; Figlewicz, Denise A.; Weitkamp, Lowell R.; Rodier, Patricia M.

doi:10.1002/1096-9926(200012)62:6<393::aid-tera6>3.3.co;2-m

Cited by 56 publications

(119 citation statements)

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“…As noted by Wolpert et al, 57 the 7p11.2-p14.1 region is adjacent to the HoxA-1 gene, which has been suggested as a candidate gene for autism. [58][59][60] A copy number variant gain was detected by the Autism Genome Project Consortium at chromosome 9p24.3. 17 Based on our haplotype sharing results for the five chromosomal regions with at least suggestive evidence of linkage results (NPLX3.18), no single haplotype was consistently shared among all affected subjects, suggesting that no single chromosomal High-density linkage in large autism pedigree K Allen-Brady et al region, or hence no single gene, explained all of the autism cases observed.…”

Section: Discussionmentioning

confidence: 99%

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

et al. 2008

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We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2-q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31-q27.3 (NPL, 4.85) and 20q11.21-q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1-p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further followup of these chromosomal regions is warranted.

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Section: Discussionmentioning

confidence: 99%

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

et al. 2008

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“…Mice with disruptions of Hoxa1 have profound alterations in hindbrain organization, [255][256][257][258] which may reflect brainstem abnormalities observed in autism. 259,260 Evidence from family studies in human populations has suggested that HOXA1 is associated with genetic susceptibility for autism, 261,262 although results have been inconsistent. 263,264 A HOXA1-related disorder, Bosley-Salih -Alorainy syndrome, has been identified in a small patient sample, with symptoms that include delayed maturation and autism.…”

Section: Mouse Models Of Environmental Contributions To Autism Etiologymentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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“…[197][198][199][200][201][202][203] HOXA1 has been shown to play a role in hindbrain development in the mouse model. 204 The first positive finding 196 was not replicated despite similar or better power in most studies. The only additional study showing an association did find A as the risk allele, 198 whereas the first study discussed the G allele and the AG/GG genotypes as risk factors.…”

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confidence: 98%

“…Owing to a reported positive association finding for the SNP rs10951154 in the homeobox A-1 (HOXA1) gene on chromosome 7p, 196 this variant was assessed in several subsequent studies. [197][198][199][200][201][202][203] HOXA1 has been shown to play a role in hindbrain development in the mouse model.…”

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confidence: 99%

The genetics of autistic disorders and its clinical relevance: a review of the literature

2006

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Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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

Cited by 56 publications

References 0 publications

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

Advances in behavioral genetics: mouse models of autism

The genetics of autistic disorders and its clinical relevance: a review of the literature

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