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Study identifies new genetic risk factors for autism

A new study published online today in the journal Nature identifies 27 genes that, if mutated, will either cause autism or contribute to its risk. The study is the most comprehensive look at the genomes of parents and children where one child is affected by autism.

“This work establishes the largest number of high-confidence genetic risk factors for autism to date and provides important insights into the underlying biology of the disorder,” said Brian J. O’Roak, Ph.D., a first author on the study and assistant professor of molecular and medical genetics in the Oregon Health & Science University School of Medicine, and member of the Institute on Development & Disability at OHSU. “Ten years ago, when I began researching autism, we never would have predicted these genes and pathways would be involved.”

O’Roak worked on the study for the past three years in collaboration with scientists at University of Washington, Yale School of Medicine and Cold Spring Harbor Laboratory, New York. O’Roak joined OHSU in late 2013 after completing a fellowship with two of the study’s senior authors, Evan Eichler, Ph.D., and Jay Shendure, M.D., Ph.D., at the University of Washington.

Scientists have been studying the genetic risk of autism for about 35 years. Recently, scientists, aided by new genome sequencing technologies, have been exploring how new or ‘de novo’ mutations might play a role — particularly in families with a single affected child and no previous history of the disorder. De novo gene mutations are formed at conception and are not present in either parent. Researchers specifically examined the ‘exome,’ a small but important part of the genome that carries the blueprints for all human proteins. The exome is thought to house 85 percent of the mutations that cause genetic disorders. Because de novo mutations in the exome originate at a child’s conception and are not shared by either parent, it’s less likely the mutation is passed from parents to future children.

“These results have immediate clinical impact. We can now guide parents in their decisions to have other children. When autism in one child occurred through a non-inherited, de novo mutation, the risk for subsequent siblings goes down to the base population rate,” said Eric Fombonne, M.D., professor of psychiatry in the OHSU School of Medicine, and director of autism research at the Institute for Development & Disability at OHSU. “We can also begin to look at different genetic subtypes within the autism spectrum.” Fombonne was not directly involved in the study.

Altogether, the study looked at more than 2,500 families with autistic children and compared children with autistic characteristics to siblings unaffected by the disorder. The families chose to take part in genetic studies through participation in the Simons Foundation Autism Research Initiative, which helped fund the study. This is the first time this large cohort of families has been analyzed genetically as a unit. Along with the 27 high-confidence risk genes, the study revealed that de novo mutations overall contribute to 25 percent of male autism diagnoses and 45 percent of female diagnoses in this cohort. Understanding why de novo mutations contribute to male and female diagnoses at different rates is currently an active area of research.

The 27 genes identified in this study represent a small but significant number of the genes associated with autism. Scientists now believe there could be approximately 400 genes associated with the disorder, with different mutations affecting each child. The type of mutation and the gene in which the mutation occurs may also play a role in how severely the disorder affects an individual child.

“Identifying the genes and types of mutations that increase autism risk will help us pursue more targeted autism research,” said O’Roak. “I am excited about the opportunity to work with my colleagues at OHSU as we build a diverse research program designed to identify the full spectrum of genes associated with autism and related disorders, understand additional environmental risk factors, develop targeted therapeutics and expand clinical interventions that help affected children and their families.”

The Simons Foundation Autism Research Initiative supported this study through grants SF191889, M144095 R11154 and SF235988. The Howard Hughes Medical Institute and the Canadian Institutes of Health Research provided additional support.

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