New autism susceptibility genes identified

Mount Sinai researchers and the Autism Genome Project Consortium (AGP) announced today that they have identified new autism susceptibility genes that may lead to the development of new treatment approaches. These genes, which include SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus, primarily belong to synapse-related pathways, while others are involved in cellular proliferation, projection and motility, and intracellular signaling. The findings were published today in Nature by researchers at the Seaver Autism Center for Research and Treatment at Mount Sinai School of Medicine, together with an international consortium of researchers who make up AGP.

"As we continue to uncover genetic mutations that can cause autism, we are gaining further insights that will ultimately lead to earlier diagnosis and better treatments," said Joseph Buxbaum, PhD, Director of the Seaver Autism Center and Professor of Psychiatry, Neuroscience and Genetics and Genomic Sciences at the Mount Sinai School of Medicine.

The study results are based on analysis of high-density genotyping data collected from 1,000 individuals with autism spectrum disorder (ASD) and 1,300 without ASD. These findings further support an emerging consensus within the scientific community that autism is caused in part by many "rare variants," or genetic changes found in less than one percent of the population.

While each of these variants may only account for a small fraction of the cases, collectively they are starting to account for a greater percentage of individuals with autism. They are also providing insights into possible common pathological mechanisms.

Findings show that the DNA of individuals with ASDs has more copy number variants (CNVs) — rare submicroscopic insertions and deletions — disrupting genes, including genes previously reported to be associated with autism, but also other genes such as those involved in intellectual disabilities. The overlap between autism susceptibility genes and genes previously implicated in intellectual disabilities further supports the hypothesis that at least some genetic risk factors are shared by different psychiatric developmental disabilities. Finally, identification of these biological pathways points to new avenues of scientific investigation, as well as potential targets for the development of novel treatments.

"It is an exciting development to see Dr. Buxbaum and colleagues identify genes that have been linked to intellectual disabilities but not previously implicated in autism now be linked to that condition as well," commented Bruce D. Gelb, MD, Director of the Child Health and Development Institute at Mount Sinai. Dr. Gelb, who was not affiliated with this study, said further, "This landmark study also provides a template for future research into the genetics of many other important human disorders."

In addition to Dr. Buxbaum, investigators at Mount Sinai were Alexander Kolevzon, MD, Medical Director of the Seaver Autism Center, Latha Soorya, PhD, Chief Psychologist of the Seaver Autism Center, and Danielle Zurawiecki, and Ana Tryfon, research coordinators at the Seaver Autism Center.

Autism is a complex neurobiological disorder that inhibits a person's ability to communicate and develop social relationships, and is often accompanied by behavioral challenges. ASDs are diagnosed in one in 110 children in the United States, affecting four times as many boys as girls. The prevalence of autism increased 57 percent from 2002 to 2006, prompting the Centers for Disease Control and Prevention to call autism a national public health crisis. A specific genetic disorder is identified in at least 15 percent to 25 percent of people with ASD, and the proportion with an etiological diagnosis will continue to increase with the widespread use of genetic sequencing studies.

Mount Sinai researchers are part of AGP, which consists of 120 scientists from more than 50 institutions representing 11 countries who formed a first-of-its-kind autism genetics consortium. AGP is co-funded by Autism Speaks, the Medical Research Council, Canadian Institutes of Health Research, Health Research Board, Genome Canada and the Hilibrand Foundation. Support for this work at Mount Sinai also comes from the Seaver Foundation. The first phase of the AGP, the assembly of the largest-ever autism DNA collection and whole genome linkage scan, was funded by Autism Speaks and the National Institutes of Health and completed in 2007. Please visit www.autismgenome.org for more information.

The Seaver Autism Center provides comprehensive assessment and care for people with autism spectrum conditions. It includes a multisciplinary team of experts which uses genetics, molecular biology, model systems, neuroimaging, and experimental therapeutics to treat each patient. The Seaver Center also provides opportunities to participate in research studies aimed at understanding the causes of autism spectrum conditions and developing treatments. For more information, visit www.SeaverAutismCenter.org.

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of few medical schools embedded in a hospital in the United States. It has more than 3,400 faculty in 32 departments and 15 institutes, and ranks among the top 20 medical schools both in National Institute of Health funding and by U.S. News & World Report. The school received the 2009 Spencer Foreman Award for Outstanding Community Service from the Association of American Medical Colleges.

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 2009, U.S. News & World Report ranked The Mount Sinai Hospital among the nation's top 20 hospitals based on reputation, patient safety, and other patient-care factors. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 530,000 outpatient visits took place.

For more information, visit www.mountsinai.org.