CNVs
Copy Number Variations (CNV)
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 disease1.
Whole genome CNV studies for genes that confer susceptibility for autism have identified many de novo genetic mutations. However, genetic CNVs are more common and likely to also contribute to the incidence of ASD. 2
Gene association methods include segment based scoring approach and a gene based scoring approach.
Segment based scoring approach
Gene based scoring approach The Gene based scoring approach examines CNV calls affecting any region of the gene.2
Citations
1. Cook, E.H. and S. W. Scherer. Copy-number variations associated wtih neuropsychiatric conditions. Nature.2008 October;455(16) 919-23. PMID 18923514
2. Glessner, JT et. al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature. 2009 May 28;459(7246):569-73 PMID 19404257
