New Research Sorting Out Risk Genes for Brain Disorders

The study provides new information about similarities and differences underlying various NDDs.

To identify and better understand gene-disrupting mutations related to NDDs, a team led by researchers of the laboratory of Evan Eichler, University of Washington Health Sciences/UW Medicine and Howard Hughes Medical Institute, conducted a large, international, multi-institutional study. More than 11,700 affected individuals and nearly 2,800 control subjects underwent targeted DNA sequencing of 208 suspected disease-risk genes, candidate genes that were chosen based on previously published studies. Samples were collected through the Autism Spectrum/Intellectual Disability 15-center network spanning 7 countries and 4 continents. An advantage of this collection is the ability to check back on a large fraction of cases in attempt to relate genetic results to clinical findings.

In their study population, the researchers associated 91 genes with risk of a NDD, including 38 genes not previously suspected. Based on some of the family studies, however, mutations even in two or more of the risk genes may not be necessary or sufficient to cause disease.

Of the 91 genes, 25 were linked with forms of autism without intellectual disability. The scientists also described a gene network that appeared to be related to high-functioning autism. Individuals with this form of autism have average to above average intelligence, but may struggle in learning to talk, interact socially, or manage anxiety and sensory overload. Additional findings suggest that less severe mutations may be behind autism that is not accompanied by intellectual disability. Also notable, although the overall numbers were low, was that several autism risk genes appeared predominantly in males, including some detected exclusively in males who had autism without intellectual impairment.

While observing that some genes were more closely associated with autism and others with intellectual or developmental impairments, the researchers found that most of the genes implicated were mutated in both conditions. This result reinforces previous studies indicating substantial overlap among NDDs in their underlying genetics and observable characteristics.

"Most of these genes are clearly risk factors for neurodevelopmental disorders in a broad sense," the researchers said, "But analysis of both the genetic and subsequent patient follow-up data did single out some genes with a statistical bias towards autism spectrum disorder, rather than an intellectual disability or developmental delay." By combining clinical and genetic data, the researchers observed patterns enabling them to begin to assess how some of the genes might function and how their disruption might lead to specific traits or symptoms.

The researchers also used Drosophila to investigate 21 genes to determine if any of the mutations disrupted a specific form of learning: habituation – growing accustomed to harmless stimuli. Problems with the neuronal mechanisms behind habituation are thought to account for some autism features, such as inability to filter sensory input. The Drosophila studies showed habituation deficits from several of the gene mutations under review, thereby providing additional evidence that they may have a role in cognitive function.

"The scientists are continuing this project and are eager to work with interested families," said University of Washington Prof. Raphael Bernier, clinical director of the Seattle Children's Autism Center. Families can contact the project team at rablab@uw.edu.

The study, by Stessman HAF et al, was published online February 13, 2017, in the journal Nature Genetics.