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Novel Mutations Linked to Autism Identified in Genes Associated with Fragile X

A new study, published in the April 26, 2012 issue of Neuron, reports the discovery of several genes associated with autism and finds evidence for a shared genetic mechanism underlying autism and fragile X syndrome, the most common genetic cause of intellectual disability. It is well established that genetic variation caused by mutation can lead to autism spectrum disorders, and research has repeatedly implicated "de novo" mutations, those that show up for the first time in affected children, as being particularly relevant. Identification of the specific genes associated with autism may lead to much needed advances in the diagnosis and treatment of autism spectrum disorders. The current study, led by Dr. Michael Wigler from Cold Spring Harbor Laboratory, used gene sequencing methods to look at nearly 350 families with healthy children and children on the autistic spectrum, part of the larger Simons Simplex Collection. Specifically, the researchers looked for mutations that were present in the children, but not in their parents. The team found that autism is linked with the types of new mutations that are likely to disrupt the function of a gene. By disrupting one of the pair of healthy genes that we normally inherit, such mutations alter "gene dosage." There was a two-fold higher incidence of such mutations in the affected child than in the healthy child, but little to no difference in the overall incidence of much more prevalent types of mutations. The results also showed that children with older parents have more new mutations. This is consistent with other recent reports and perhaps explains why older parents are more likely to have children on the autism spectrum. "More generally, this work and the work preceding it point to the importance of new mutations and gene dosage in so-called complex genetic disorders," says Dr. Wigler. Importantly, the study also identified many new autism candidate genes, and these genes showed a strong overlap with genes linked to the pathway involved in fragile X syndrome, one of the best studied cognitive-behavioral disorders in humans. "We observe strong statistical evidence for the link between autism and fragile X syndrome, first suggested by study co-authors Dr. Jennifer Darnell and Dr. Robert Darnell, in a paper they published in Cell last year," explains Dr. Wigler. "Our finding has important implications for therapy and shows that autism is in large part a molecular disorder of neuroplasticity, the mechanisms by which our nervous system adapts to change." [Press release] [Neuron abstract]