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A Better Early Blood Test for Autism: Genetic signatures point to disrupted neuro-immune pathways

Researchers at Boston Children's Hospital have developed a blood test for autism spectrum disorders (ASDs) that outperforms existing genetic tests, while presenting evidence that abnormal immunologic activity affecting brain development may help explain some of autism's origins. The findings also suggest a new direction for genetic research on autism and the search for treatments.

The blood test, described December 5 in the online open access journal PLOS ONE and based on the largest gene-chip investigation ever done in autism, could enable early diagnosis of autism in about two thirds of patients before clear symptoms start to appear (the average age of diagnosis in the U.S. is 5 years).

Researchers led by Sek Won Kong , MD, of the Boston Children's Hospital Informatics Program (CHIP) analyzed blood samples from 66 male patients with ASDs (from Boston Children's and several other hospitals in collaboration with the Autism Consortium of Boston) and compared them with 33 age-matched boys without ASDs. Using microarrays, they looked for RNA signatures reflecting differences in gene activity, or expression, between the two groups.

"Since brain biopsy isn't a viable option for research, we asked whether blood could serve as a proxy for gene expression in the brain," says Isaac Kohane , MD, PhD, director of CHIP and senior investigator on both studies. "We found that it could, though we and others were initially skeptical."

Analyzing the blood samples, Kong and colleagues flagged 489 genes as having distinct expression patterns in the ASD group, then narrowed this to a group of 55 genes that correctly identified or ruled out autism in 76 percent of samples. They validated their findings in a second group of 104 male and female patients with ASDs and 82 controls, achieving an overall classification accuracy of 68 percent (73 percent for males and 64 percent for females).

The gene signature approach, which Boston Children's Hospital has licensed exclusively to SynapDx (Southborough, Mass.), can potentially diagnose autism far more often than the genetic tests currently available. Those tests look for variety of autism-related mutations, from small "spelling" changes to lost or extra copies of a gene or genes (known as copy number variants) to wholesale chromosome abnormalities, but together, the known mutations account for fewer than 20 percent of autism cases.

"It's clear that no single mutation or even a single pathway is responsible for all cases," says Kohane. "By looking at this 55-gene signature, which can capture disruptions in multiple pathways at once, we can say with about 70 percent accuracy, 'this child does not have autism,' or 'this child could be at risk,' putting him at the head of the queue for early intervention and evaluation. And we can do it relatively inexpensively and quickly."

Previous gene-expression studies on blood samples have been limited by study size and by the challenge of obtaining well-matched control groups, Kohane notes.

The 55 genes whose expression was altered also suggest more than one path to what we know as autism. Based on their genetic signatures, subjects with ASDs clustered into four subgroups marked by changes in different biological pathways: Synaptic pathways, specifically long-term potentiation pathways (essential for memory and learning) and neurotrophic pathways (signaling neurons to survive, develop and grow) and immune/inflammatory pathways.

"In our sample, about half of the autism cases had some sort of alteration on immune pathways, synaptic pathways, or both," says Kong.

Adding to the neuro-immune theory of autism

Most current theories of autism focus on disordered synapses (connections between brain cells). But, citing previous studies in the medical literature, Kohane speculates that brain development in autism may be impaired by abnormal immune responses to infections and other stressors, during infancy or prenatally. For example, chemokines (inflammatory chemical messengers that recruit immune cells to fight infections) have been found to be overexpressed in some neurocognitive disorders, and animal studies have found that prenatal infections are associated with autism-like features in offspring.

"We know that if a mother has rheumatoid arthritis or the father has type 1 diabetes, there is an increased risk of autism in the child," says Kohane. "Studies have also noted an increase in autoimmune disease, just as autism is increasing."

Previous studies of brain tissue from patients with autism have found significant activation of immune cells in the cerebral cortex and cerebellum, and recent research at Boston Children's Hospital has shown that the same molecules used by the immune system also play a role in the development and functioning of the brain.

"One can imagine that an infectious assault during pregnancy could increase chemokines into the brain," Kohane says. "Or there may be something intrinsic to the brain that causes it to generate an inflammatory reaction. Genetic makeup may set up vulnerability in a subgroup of infants, but there may be some environmental factor that triggers the disease in that subgroup."

The blood test was developed under grants from the Simons Foundation, the Nancy Lurie Marks Family Foundation, Autism Speaks, the Howard Hughes Medical Institute, the Autism Consortium (NIMH grant #R01MH085143, the Molecular Genetics Core laboratory supported by NICHD (grant #P30HD018655), and the Charles H. Hood Foundation.

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Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395-bed comprehensive center for pediatric and adolescent health care.

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