High-throughput sequencing shows potentially hundreds of gene mutations related to autism

December 19, 2012

Genomic technology has revolutionized gene discovery and disease understanding in autism, according to an article published in the December 20 issue of the journal Neuron.

The paper highlights the impact of a genomic technology called high-throughput sequencing (HTS) 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 the article in 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, Broad Institute and Harvard Medical School; Bernie Devlin, University of Pittsburgh; Thomas Lehner, National Institute of Mental Health; Kathryn Roeder, Carnegie-Mellon University; Matthew W. State (co-director), Yale University, and the ASC.

HTS is a revolutionary new technology that allows scientists to obtain the sequence of all 22,000 human genes and the entire human genome in one experiment. This provides an unparalleled look at an individual's genetic makeup and allows for gene discovery and for genetic testing.

"HTS shows us that there are not just a few mutations, but potentially hundreds of mutations that are linked to autism," said 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."

Ground-breaking, highly reproducible discoveries identified through HTS described in the article include: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 (WES) or whole genome sequencing (WGS) in large cohorts. The exome is the small fraction of the genome that codes for proteins.

The article spotlights the successful work of the ASC, founded in 2010, as a model to bring to fruition an explosive gene discovery process. The ASC member sites, using WES technology also available at Mount Sinai, recently discovered six de novo mutations in autism patients: CHD8, DYRK1A, GRIN2B, KATNAL2, POGZ and SCN2A. These six genes may be targets for future treatments. Some of these discoveries were accomplished rapidly because the Consortium's 25 research groups, located around the world, combined their data and shared it before publication. As a result, they conducted four large studies using 1,000 families.

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. The ASC was designed to address these issues, and Mount Sinai has created Minerva, one of the largest academic supercomputers in the world, to help with these goals.
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The research conducted at Mount Sinai was supported by grants from the National Institutes of Health and the Seaver Foundation.

About Autism Spectrum Disorder

ASD is a developmental disability that causes significant language delays, and social and communication challenges, and affects one in 88 children, according to the U.S. Centers for Disease Control and Prevention. There is no cure for autism and some researchers are probing possible environmental causes of the disorder. But, gene mutations are today considered the key cause of autism, so discovering new genes related to autism is crucial in finding novel treatments.

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai. Established in 1968, the Icahn School of Medicine is one of the leading medical schools in the United States, and is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.

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