Autism genetics study finds correlation between mutations and complex health profiles

September 3, 2015
Genetic mutations linked to autism are more common in children who have ASD alongside other disabilities or impairments.
In a paper published in JAMA this week, “Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children,” researchers found 16% of the 258 children in the study, all of whom had an ASD diagnosis, also had autism-linked genetic mutations.
Lead author Bridget A. Fernandez points to findings among the most severely affected children, who also have major facial differences, or conditions such as cleft palate or heart abnormalities as the most significant insights emerging from the research. “The children were put into three groups based on severity,” she said.  “And when we did that, the children in the [most] complex group – 35% of them had a genetically positive test.”
Autism diagnosis in this complex group was more delayed than in children without additional disabilities, according to Fernandez, most likely because other presenting concerns made red flags for autism less noticeable.
The research team, which included NeuroDevNet investigators Wendy Roberts, Rosanna Weksberg, Lonnie Zwaigenbaum, Stephen Scherer and Evdokia Anagnostou, Peter Szatmari and former NeuroDevNet doctoral trainee Dr. Anath Lionel, used two forms of genetic diagnostics in the study: chromosomal microarray analysis, a microchip-based testing platform that allows high-volume, automated analysis of many pieces of DNA at once; and whole exome sequencing – a next-generation technology that determines variations of all coding regions, or exons, of known genes.
“Sixteen percent had an ASD-significant finding on either the microarray or the whole exome sequencing,” said Fernandez.
NeuroDevNet investigator Dr. Stephen Scherer has recently published papers using whole genome sequencing to study genetic mutations associated with autism, where known genetic mutations detected ran to 50% among the children in the study, and 10% in another study of children with cerebral palsy.
While such cutting edge technologies are available to leading researchers, they are a long way from clinical application, according to Dr. Zwaigenbaum. “It’s important to take the historic perspective on exome findings. The reality is, in Canada, we have only very recently been having access as clinicians to microarray testing.”
Several layers of referrals from geneticists are necessary in Alberta, where he practices, before a family can access microarray testing for a child, he said.  
It seems likely that genetic testing of children with ASD will continue to increase, the authors conclude, drawing on a previous survey that found 80% of parents would want a sibling younger than 2 years tested to identify ASD-risk mutations even if the test could not confirm or rule out the diagnosis.
That 6 percent of children with no other evidence of abnormalities had ASD-associated mutations means the findings have important implications for the care and treatment of children who have siblings with ASD, as well as family counseling,  Zwaigenbaum said.
“If we can understand the underlying genetics more completely,” added Fernandez, “we have to possibility to identify at-risk children through genetic testing and get earlier diagnosis to improve the outcomes.”

Quotes from Dr. Fernandez were derived from a Sept. 1 JAMA Network video

Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children
JAMA. 2015;314(9):895-903. doi:10.1001/jama.2015.10078