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GEN News Highlights : Dec 20, 2012
Hundreds of Mutations Potentially Linked to Autism
A research team reports that high-throughput sequencing (HTS) played an essential role in discovering numerous new genes that are associated with autism spectrum disorder (ASD).
"These new discoveries using HTS confirm that the genetic origins of autism are far more complex than previously believed," said Joseph D. Buxbaum, PhD, director of the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai, and lead author of an article in the December 20 issue of Neuron.
Dr. Buxbaum is co-founder and co-director of the Autism Sequencing Consortium (ASC), a large multisite collaboration which is a model for future research. The co-authors of the article are Mark J. Daly, Ph.D., Broad Institute and Harvard Medical School; Bernie Devlin, Ph.D., University of Pittsburgh; Thomas Lehner, Ph.D., National Institute of Mental Health; Kathryn Roeder, Ph.D., Carnegie-Mellon University; Matthew W. State, M.D., Ph.D. (co-director), Yale University, and the ASC.
"HTS shows us that there are not just a few mutations, but potentially hundreds of mutations that are linked to autism," continued Dr. Buxbaum. "By identifying the many genetic roots of this disorder, we can better understand its biology, which in turn will allow us to develop more tailored treatments for individuals. It is a transformative time for genetic research in autism."
Other discoveries in the article include the "staggering degree" of genetic heterogeneity in autism, which means that many individuals with autism do not share similar gene mutations; the identification of an increasing number of specific genes and chromosomal intervals conferring risk; the important emerging role in autism of both rare and "de novo germline mutations," or mutations developed in the sperm or ovaries of parents and passed on to children; and gene loci associated with autism that overlap with gene loci associated with other illnesses, such as intellectual disability and epilepsy.
Dr. Buxbaum estimates that researchers have already identified 50 specific genes and 20–40 chromosomal loci conferring risk. The researchers predict, based on the first studies in 1,000 families, that there are many hundreds of undiscovered ASD associated genes. This surge in the number of genes related to autism revealed by HTS marks a coming of age for high-throughput sequencing, the authors believe.
The path forward for new discoveries, they write, is via one of two HTS processes: whole exome sequencing or whole genome sequencing in large cohorts. The exome is the small fraction of the genome that codes for proteins.
There are approximately 8,000 to 10,000 families currently available to the consortium to study autism, but the article suggests many more are needed to speed up gene discoveries. Also needed for the future is increased collaboration among research teams and the integration of autism studies with studies of other psychiatric disorders. In addition, high-capacity supercomputers are needed to analyze the data.
In 2012, the Centers for Disease Control and Prevention’s Autism and Developmental Disabilities Monitoring Network reported that approximately 1 in 88 children in the U.S. has an ASD, according to the Autism Science Foundation. This represents an increase in the prevalence of ASDs compared to earlier in the decade when prevalence was cited as 1 in 110 and 1 in 166. In the 1980s autism prevalence was reported as 1 in 10,000. In the nineties, prevalence was 1 in 2,500 and later 1 in 1,000.
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