Genetics

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Genetics

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CadherinsNeuroligins/Neurexins/Shank3
METCNVs
ERK and P13KUbiquitin
RELNNeurotrophins
CNTNAP-2Serotoninergic, GABAergic,
and glutamatergic pathways
EIF4EPTEN
NeurotrophinsOxytocin and AVP
DIAPH3
Anaphase IF.gif


A host of genes of interest have been identified through gene association studies, resequencing and, recently, the assessment of copy number variation (CNV).In particular, given the pathology of ASD, genes dealing with electrical conductance and neural transmission have been popular sites of study since synaptic dysfunction has been suggested as a unifying theme behind the various disorders in ASD. It has been difficult to find a specific gene mutation that is present in all cases of ASD, probably because of the heterogeneity of the ASD population. However, one group found that when they stratified an ASD group into subgroups based off of severity of symptoms and applied cluster analysis and various genetic profiling techniques, there were 20 novel genes that were shared by all three ASD subgroups. Additionally, most of the highly significantly differentially expressed genes in the ASD group that was found in the study are differentially regulated within the context of androgen insensitivity. This supports one hypothesis that higher levels of fetal testosterone are a risk factor for ASD.1

The high occurrence of differential expression profiles for 15 clock genes only for those in the severely affected ASD subgroup suggest that the severity of symptoms may be a connected with the dysregulation of the circadian rhythm. Scientists have demonstrated a genetic association of PER1 and NPAS2 with autistic disorder, and other theories have been proposed interplays between Fragile-X related proteins and synaptic genes with circadian rhythm genes.1

Most approaches to finding loci of interest are under one of two assumptions:

  1. ASD is a result of interplay between many genes
  2. There is one principle gene which contributes to many aspects of the disease.

The idea that the symptoms of ASD is a result of the interaction of many different genes has been supported by linkage studies, and the fact that although many genes have been identified with causing ASD symptoms, each of these individual genes do not cause more than 1-2% of all ASD cases. However, data mining techniques such as hierarchical clustering and principle components analysis find that it is highly likely that there is 1 continuously distributed factor contributing to many aspects of ASD, thereby validating the existence of the second hypothesis. Additionally, statistical analysis of ASD family data suggest a large portion of ASDs may be the result of dominant de novo mutations that have reduced penetrance in families.

Methylation-One other hypothesis that may account for the widespread genetic defects found in ASD patients is that there may be abnormal methylation of brain-expressed genes on the X chromosome which in turn causes abnormal expression levels of genes important during development. These alternations cause one or more genes on the single X chromosome in males to be either partially silenced or over-expressed. This similarly happens in females, but the random X-chromosome inactivation might lesson autism predisposition and prevalence in females. This proposal is consistent with the findings that males make up a significantly larger amounts of ASD cases than females.2

Genetics continued...

Citations

1. Schmitz C. Autism: neuropathology, alterations of the GABAergic system, and animal models.Int Rev Neurobiol. 2005;71:1-26. PMID 16512344

2. Jones, J.R. et. al. Hypothesis: Dysregulation of Methylation of Brain-Expressed Genes on the X Chromosome and Autism Spectrum Disorders. American Journal of Medical Genetics Part A 146A:2213-2220 (2008). PMID 18698615

3. Lush, Molly et. al. Current Developments in the Genetics of Autism: From Phenome to Genome. J Neuropathol Exp Neurol. 2008 September; 67(9):829-837. PMID 18716561

4. Cook, E.H. and S. W. Scherer. Copy-number variations associated wtih neuropsychiatric conditions. Nature.2008 October;455(16) 919-23. PMID 18923514

5. Hoekstra RA, et. al. Autistic traits in simplex and multiplex autism families: Focus on unaffected relatives.Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):356-8. PMID 19367575