Copy number variation CNV A paradigm shift in autism

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The strong genetic contribution shown in family studies and the association of cytogenetic changes, but apparent lack of common risk factors in autism, led to a hypothesis that rare sub-microscopic unbalanced changes in the form of CNVs likely contribute to the autism phenotype. With the development of microarrays capable of scanning the genome at sub-microscopic resolution, there is accumulating evidence that multiple CNVs contribute to the genetic vulnerability to autism [80]. de novo CNV has been identified in up to 7-10% of sporadic autism [81, 82], but are less frequent in multiplex families, in which CNV accounts only for about 2% of families screened [80, 83]. This could possibly suggest different genetic liabilities in simplex and multiplex autism. Recurrent CNVs at 15q11-13 (1-3% of autism patients), 16p11 (1% of autism patients), and 22q11-13 have been confirmed in multiple studies [80, 83-86]. This hypothesis also has been proven largely successful in identifying autism-susceptibility candidate genes, including gains and losses at SHANK2 [87], SHANK3 [88], NRXN1 [13], NLGN3 and NLGN4 [37], and PTCHD1 [89, 90]. Neurexins and neuroligins are synaptic cell-adhesion molecules (CAMs) that connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. The Shank family of proteins provides scaffolding for signaling molecules in the postsynaptic density of glutamatergic synapses. Genes encoding CAMs play crucial roles in modulating or fine-tuning synaptic formation and synaptic specification. Localization and interacting proteins at the synapse is shown in Figure 1.

Figure 1. Localization of cell-adhesion molecules and their interacting proteins at the synapse. Proteins associated with ASD are underlined.

It is apparent that many different loci, each with a presumably unique yet subtle contribution to neurodevelopment, underlie the phenotype of autism. These observations have resulted in a paradigm shift away from the previously held "common disease-common variant" hypothesis to a "common disease-rare variant" model for the genetic architecture of autism. The central tenet of this model suggests a role for multiple, rare, highly penetrant, genetic risk factors for ASD, many of which are in the form of CNV. To make sense of the contribution of CNVs to autism, a "threshold" model has been proposed [80]. The model posits that different CNVs exhibit different penetrance depending on the dosage sensitivity and function (relative to autism) of the gene(s) they affect. Some CNVs have a large impact

Figure 1. Localization of cell-adhesion molecules and their interacting proteins at the synapse. Proteins associated with ASD are underlined.

on autism susceptibility and these are typically de novo in origin, cause more severe autistic symptoms, are more prevalent among sporadic forms of autism, and are less influenced by other factors like gender and parent of origin. Other CNVs have moderate or mild effects that probably require other genetic (or non-genetic) factors to take the phenotype across the autistic threshold.

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Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

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