Copy-Number Variation
Copy Number Variation and ASD
CNVs in certain dosage sensitive genes have been suggested as the root cause of ASD. This theory is particularly appealing because CNVs have a high locus-specific rate of new nucleotide mutations, 3-4 times the rate for single nucleotide polymorphisms. Additionally, CNVs can account for the phenotypic variation seen in ASD. The type of copy number rearrangement and whether it was inherited maternally or paternally can further affect the phenotype. For example, duplications of chromosome 15q11-q13 that are derived maternally confers a high risk of ASD (>85%) while those inherited paternally have anywhere from no phenotypic affects to mild developmental and cognitive impairment. There is relative enrichment within CNVs for neuronal synaptic complex genes, particularly SHANK3, NLGN4, and NRXN1. However, it is difficult to know right now how harmful a particular inherited CNV will be because the extent of the CNV and what genes are included, as well as which geens are nearby can influence the phenotypes. Specifically, other genes can modulate the risk of genes that normally confer genes, and other genes can even act protectively to decrease the risk of developing a particular genetic disease4.
Some likely candidate genes that have been explored include
| Gene | Function | Location | source |
|---|---|---|---|
| UBE3A | transcribed protein is an enzyme that works in protein degradation | 15q11-q13 | PMID 18414403 |
| GABRB3 | encodes a member of of a ligand gated ionic channels responsible for inhibition in nervous system | 15q11-q12 | PMID 18414403 |
| MET | encodes receptor tyrosine kinase involved in neuroal growth and organization, immunological and gastrointestinal functioning | 7q31 | PMID 18716561 |
| SLC6A4 | serotonin transporter | 17q11 | PMID 18716561 |
| RELN | encodes protein that controls intercellular interactions involved in neuronal migration and positioning in brain development | 7q22 | PMID 18716561 |
| CNTNAP2 | part of neurexin superfamily, encodes CASPR2, a transmembrane scaffolding protein | 7q35-q36 | PMID 18179894 |
Analytical Techniques
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
