Researchers have taken a critical step in improving genetic diagnostic testing for children with autism spectrum disorders. Armed with data from 30,000 individuals with neurodevelopmental disorders who had undergone clinical genetic testing as well as 4,000 children enrolled in studies of autism spectrum disorders (ASD), they identified 30 new specific genetic mutations that increase risk for neurodevelopmental disorders. Eighteen of these mutations are found in autism, of which 10 would have been missed using conventional approaches. All of these mutations can now be used as diagnostic markers.
For years, researchers have known that submicroscopic variations in chromosomal structure, called copy number variations (CNVs), can cause autism. However, CNVs are also often present in typically developing children and children with other neurodevelopmental disorders. A collaborative team including researchers from Emory, Yale, UCLA and Geisinger Health System took the novel approach of combining extensive clinical testing data with research cohorts to clarify which genetic findings were relevant to ASD.
The study appears online October 9, ahead of publication in the journal Molecular Psychiatry. Daniel Moreno De Luca, MD, MSc, a current first-year psychiatry resident at Yale School of Medicine, is lead author.
Many of these newly categorized CNVs would not appear frequently enough in existing ASD research cohorts to be considered statistically significant for the group as a whole. But, for individuals in whom these CNVs are found, they are highly relevant, with important implications for clinical care.
"The genetics of autism are very heterogeneous with no more than 1-2% of individuals sharing the same genetic etiology. Our findings have important implications, because establishing the clinical role of CNVs in large populations allows us to then identify the same CNVs in individuals with autism, informing clinical care decisions," said Moreno De Luca. "Starting from the combined clinical datasets was crucial. Without that starting point, we would have missed the relevance of several CNVs given their low frequency in groups of people with autism."
Genetic data from more than 30,000 clinical cases was merged to create a powerful new cohort to analyze for rare CNVs that contribute to neurodevelopmental disorders, including ASD.
In a second step, researchers compared the statistically significant CNVs from this large dataset against a cohort of close to 4,000 autism patients from three of the largest autism collections worldwide. This novel approach allowed investigators to uncover clinically significant CNVs that had been overlooked in previous analyses.
Additional Yale authors on the study include Stephan J. Sanders, MD, A. Jeremy Willsey, BSc, and Matthew State, MD, PhD.
Senior authors of the study were David H. Ledbetter, PhD, at Geisinger Health System, and Christa L. Martin, PhD, at Emory University School of Medicine.
The work was funded by the National Institutes of Health and the Simons Foundation with support from the Autism Genetic Resource Exchange (AGRE), a science program of Autism Speaks.