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A Better Early Blood Test for Autism
Posted on:
December 20, 2012
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 this month 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)
-- 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.
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