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Genetic Findings in Autism Could Lead to Personalized Therapy

NEW YORK (GenomeWeb) – Advances in genetic technologies have led to dramatic progress in piecing together the molecular etiology of autism spectrum disorder and are pointing the way toward better therapeutics, according to researchers from the University of California, Los Angeles and the University of California, San Francisco.

The researchers published a review article in Lancet Neurology this week as part of a series of articles the journal is publishing on autism.

Despite being a complex condition caused by both genetic and environmental factors, genetic research "has taken the leading role in the elucidation of pathophysiology," the authors wrote. In addition, they said the multitude of genes that are being discovered that play a role in autism appear to be converging on a handful of pathways: chromatin modification, synaptic function, targets of fragile X mental retardation proteins, targets of RBFOX splicing factors, and early embryonic development. Treatments that target these pathways could potentially lead to better outcomes, they reported.

The authors said that while the early days of genetic research focused on linkage analysis to identify signals from common variants, most of the major gene discoveries have come in recent years due in part to advances in next-gen sequencing technology, and have been of rare, highly penetrant mutations and copy number variants.

Next-gen sequencing technology has enabled unbiased assessments of whole genomes and exomes. Currently, there are a number of studies seeking to analyze large cohorts of patients with autism, including Kaiser Permanente's Autism Research Program, which aims to create a database of 5,000 family trios, and the MSSNG project, a collaboration between Autism Speaks, the Hospital for Sick Children in Toronto, and Google that as of last summer had sequenced more than 1,000 samples and had 2,000 more lined up.

As a result of these types of studies, new findings are occurring at a rapid rate. Just last month, researchers from Johns Hopkins University reported that sequencing the exomes of 12 severely affected girls led to the discovery of four candidate genes. In addition, an analysis published last year of over 1,000 children that generated exome sequencing and array-CGH data led to the identification of 12 new disease genes, researchers at the Wellcome Trust Sanger Institute reported. 

The authors of the Lancet Neurology article argued that these types of genetic advances point to autism as a "common syndrome" that is comprised of "several hundred rare disorders."

The next step will be to translate these findings into better treatment options. For instance, there is some evidence that a subset of autism genes become affected during fetal development, they wrote, and as such, "a pressing question is how and whether effective treatments can be developed to target core symptoms."

In addition, around one in four children with autism will develop seizures and often respond to epilepsy drugs. "Available data suggest that at least some forms of ASD involve time-specific developmental deficits as well as ongoing alterations in [central nervous system] functioning that might present targets for treatment," the authors wrote.

Going forward, genetic diagnosis could play a role in determining patient care and appropriate therapies.

"One can easily imagine that the combination of routine clinical sequencing with expansive clinical databases will open new vistas in understanding the genetics, phenomenology, and comorbidities of ASD," the authors wrote.