Sorting out risk genes for brain development disorders

February 23, 2017, University of Washington
A laboratory at UW Medicine in Seattle where DNA research is underway to better understand genetic risks of disease. Credit: Clare McLean

Gene discovery research is uncovering new information about similarities and differences underlying various neurodevelopmental disorders.

These are a wide-ranging collection of conditions that affect the brain. They include , intellectual impairments, developmental delays, attention deficits, tic disorders and language difficulties.

To better understand how gene-disrupting mutations contribute to the biology of neurodevelopmental disorders, researchers recently 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. The were chosen based on previously published studies.

By looking at greater numbers of cases and using a reliable yet inexpensive molecular inversion probe, the project team wanted to measure the statistical significance of individual, implicated genes.

Their results are reported in Nature Genetics. The study leaders were Holly A. F. Stessman, Bo Xiong and Bradley P. Coe, of the genome sciences laboratory of Evan Eichler at the University of Washington School of Medicine and the Howard Hughes Medical Institute. Stessman is now at Creighton University.

Their samples were collected through the Autism Spectrum/Intellectual Disability 15-center network spanning seven countries and four continents. An advantage of this collection, the researchers said, is the ability to check back on a large fraction of cases to try to relate genetic results to clinical findings.

In their study population, the researchers associated 91 genes with the risk of a neurodevelopmental disorder. These included 38 genes not previously suspected of playing a role. 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.

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 the substantial overlap among these conditions in their underlying genetics and observable characteristics.

"Most of these genes are clearly risk factors for in a broad sense," the researchers explained. "But analysis of both the genetic and subsequent patient follow-up data did single out some genes with a statistical bias towards , rather than an intellectual disability or developmental delay."

Additional findings suggest that less severe mutations may be behind autism that is not accompanied by .

By following up with patients, the researchers could start to assess the newly discovered mutations. Such clinical information is important in determining how the genes might function, and how their disruption might lead to specific traits or symptoms.

In addition to looking at the overall severity of each neurodevelopmental disorder present, the scientists also summarized other features such as seizures, head size, and congenital abnormalities.

The researchers did in fact observe patterns from combining clinical and genetic data. They partitioned those genes most strongly associated with autism, and those more related to developmental disabilities.

Although the overall numbers were low, several autism risk genes appeared predominantly in males, including some detected exclusively in males who had autism without intellectual impairment.

To obtain additional evidence for how risk genes might affect behavior and nervous system function, the researchers investigated 21 in fruit fly models. They wanted to see if any of the mutations disrupted a fundamental form of learning—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 fruit fly 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.

Numerous grants and other funding from government agencies and private foundations in several countries supported this research.

"The scientists are continuing this project and are eager to work with interested families," said Raphael Bernier, associate professor of psychiatry and behavioral sciences and clinical director of the Seattle Children's Autism Center and associate director of the UW Center on Human Development and Disability.

Explore further: Genetic cause identified for previously unrecognized developmental disorder

More information: Holly A F Stessman et al, Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases, Nature Genetics (2017). DOI: 10.1038/ng.3792

Related Stories

Genetic cause identified for previously unrecognized developmental disorder

December 22, 2016
An international team of scientists has identified variants of the gene EBF3 causing a developmental disorder with features in common with autism. Identification of these gene variants leads to a better understanding of these ...

Mutations in life's 'essential genes' tied to autism

December 12, 2016
Genes known to be essential to life—the ones humans need to survive and thrive in the womb—also play a critical role in the development of autism spectrum disorder (ASD), suggests a new study from Penn Medicine geneticists ...

Unique genetic basis found in autism genes that may lead to earlier diagnosis

October 6, 2016
Ben-Gurion University of the Negev (BGU) researchers are a step closer to understanding the genetic basis of autism, which they hope will lead to earlier diagnosis of what is rapidly becoming the most prevalent developmental ...

Researchers find alterations of a single gene associated with intellectual disability, epilepsy and autistic features

October 7, 2011
(Medical Xpress) -- Virginia Commonwealth University School of Medicine researchers, working with an international team of colleagues, have identified a gene that may play a role in causing a neurodevelopmental disorder that ...

Researchers find new genetic pathway behind neurodevelopmental disorders

December 6, 2012
Researchers at the Douglas Mental Health University Institute, have discovered a new genetic process that could one day provide a novel target for the treatment of neurodevelopmental disorders, such as intellectual disability ...

Team first to map autism-risk genes by function

November 21, 2013
Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to increased autism risk. Where do you start?

Recommended for you

Critical role of DHA on foetal brain development revealed

August 17, 2018
Duke-NUS researchers have found evidence that a natural form of Docosahexaenoic Acid (DHA) made by the liver called Lyso-Phosphatidyl-Choline (LPC-DHA), is critical for normal foetal and infant brain development, and that ...

Gene silencing critical for normal breast development

August 17, 2018
Researchers have discovered that normal breast development relies on a genetic 'brake', a protein complex that keeps swathes of genes silenced.

New algorithm could improve diagnosis of rare diseases

August 17, 2018
Today, diagnosing rare genetic diseases requires a slow process of educated guesswork. Gill Bejerano, Ph.D., associate professor of developmental biology and of computer science at Stanford, is working to speed it up.

Officials remove special rules for gene therapy experiments

August 16, 2018
U.S. health officials are eliminating special regulations for gene therapy experiments, saying that what was once exotic science is quickly becoming an established form of medical care with no extraordinary risks.

Genetic link discovered between circadian rhythms and mood disorders

August 15, 2018
Circadian rhythms are regular 24-hour variations in behaviour and activity that control many aspects of our lives, from hormone levels to sleeping and eating habits.

Ovarian cancer genetics unravelled

August 14, 2018
Patterns of genetic mutation in ovarian cancer are helping make sense of the disease, and could be used to personalise treatment in future.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.