No evidence for linkage of liability to autism to<i>HOXA1</i>in a sample from the CPEA network

Devlin, Bernie; Bennett, Pamela J.; Cook, Edwin H.; Dawson, Geraldine; Gonen, D.; Grigorenko, Elena L.; McMahon, William M.; Pauls, David L.; Smith, Moyra; Spence, M. Anne; Schellenberg, Gerard D.

doi:10.1002/ajmg.10603

Cited by 32 publications

(18 citation statements)

References 40 publications

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“…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. 265 Gene expression profiles in normal and Hoxa1 À/À embryonic stem cells have shown that Hoxa1 regulates expression of Bdnf and other genes important for development.…”

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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Section: Mouse Models Of Environmental Contributions To Autism Etiologymentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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“…182 One group found aberrant forms of HOXA1 and HOXB1 in a survey of autistic families, 179 but this was contradicted by additional studies. [183][184][185] This does not rule out the involvement of other Hox genes as causes of autism, however. Manning et al 186 reported a lower ratio of second to fourth digit length in families with autism, possibly reflecting derangement of prenatal testosterone levels as a result of mutations in HOXA13 or HOXD13.…”

Section: Hypothesis Driven Studies: the Search For Candidate Genesmentioning

confidence: 99%

The Genetics of Autism

2004

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ABSTRACT. Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of ϳ3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is ϳ2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affec...

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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.…”

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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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No evidence for linkage of liability to autism toHOXA1in a sample from the CPEA network

Cited by 32 publications

References 40 publications

Advances in behavioral genetics: mouse models of autism

Advances in behavioral genetics: mouse models of autism

The Genetics of Autism

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

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