say. Already, some labs are working to
find chemical markers of the disorder
that could be used for early diagnosis.
Other laboratories are using new technologies to sequence all protein-coding
regions and even all of a person’s DNA to
identify parts of the genome that diverge
in people with autism and healthy subjects. As researchers home in on genomic
differences that can predispose an individual to autism, ways to tailor treatments and interventions may emerge.
“It’s someplace where we’ve been 30 or
50 years behind other areas of medicine,”
says State, a specialist in child psychiatric
disorders. “If you go to a cardiologist, they
understand the pathology that they look
at in the clinic at a molecular and cellular
level. In autism and other child psychiatric disorders, we have not had that.”
Multiple rare syndromes
Autism is not one disorder, but a spectrum of disorders. People with autism
often have great difficulty with communication and social interaction. Some
cannot speak or maintain eye contact.
Many have repetitive routines. A common trait is obsessive attention to certain details. Symptoms can be mild
to severe, and about half of kids with
autism have some kind of intellectual
disability. In the United States, an estimated one in 110 children has an autism
c. Be TancUr et Al/treNds iN NeuroscieNces, aDaP TeD By e. Feliciano
For years, most studies focused on
finding common variations in a handful of genes. While researchers found a
few genetic variants linked to autism,
the cumulative effects were disappointingly small, accounting for just a fraction
“The hypothesis had been that in
order for a common disease to arise,
you would need to have common genetic
variations in perhaps just a few genes,”
says Stephen Scherer, director of the
Center for Applied Genomics at the Hos-
pital for Sick Children in Toronto. “But
that idea is shifting.”
One reason for the shift: Following
the completion of the Human Genome
Project in 2003, it became apparent that
the genome is much more variable than
previously thought. Studies showed that
the number of copies of a particular gene
differs from one individual to the next.
Many of these variations involve either
segments of DNA that are entirely missing from the genome or the same segment repeated several times.
Through such gains or losses, called
copy number variations, whole stretches
of DNA can be erased or repeated (SN:
7/3/10, p. 12). Most copy number variants appear to be harmless. But some
can remove parts or all of a gene. Studies
have implicated copy number mutations
in a number of diseases, including schizophrenia. And in 2007, researchers at Cold
Spring Harbor Laboratory in New York
found evidence that such anomalies may
also be associated with the symptoms of
autism spectrum disorders.
Researchers then began looking for
rare variants in autism—and found
them. In a widely acclaimed study in the
July 15 Nature, an international group
of researchers compared genomes of
nearly 1,000 autistic people and about
1,300 healthy controls. The scientists
found dozens of genes were involved.
Most of the variants were sections of
DNA that were either duplicated or
missing. Some of the genetic changes
were inherited from the kids’ parents,
while other variants were new, arising
from alterations of DNA in the egg or
sperm of one of the parents, or in the
Those findings support an emerging
consensus within the scientific community, says Scherer, who coauthored the
study. Namely, that autism, instead of
having just one or two genetic risk factors, probably has hundreds.
“I think it says something fundamental
about autism, that you can think of it as
a collection of rare syndromes,” he says.
Scientists now suspect that, while
the number of different genes involved
is large, the protein products of these
genes participate in a much smaller
number of common pathways that regulate brain development and function.
Two genes may encode two proteins
that seem totally unrelated but, in fact,
interact closely in a particular pathway.
A deficiency in either’s function could
result in the same outward defect.
That seems to be what’s happening,
Scherer says. While each of the variants
may account for only a small fraction
of autism cases—no single variant
can be said to account for more than
1 percent—collectively the rare
variants may account for a large fraction of the cases.
Scientists are now working to identify
all of the genes involved and create a catalog of autism risk genes. Studies to date
have already identified 100 or so strong
candidate genes. And Scherer and his
colleagues recently completed a second
study with an additional 1,500 families,
with analysis of the data now underway.
Getting the message Projections called axons transmit messages from one nerve cell to
another (left) at the synapse (right), a junction between nerve cells held in place with the aid of
various cell-adhesion molecules. studies have linked autism with mutations in a number of genes
involved in cell adhesion at the synapse. a disruption in any one of the proteins (dark purple) that
these genes code for may throw off the system so that nerve cells don’t connect normally.
Presynaptic Neurexin SHANK Proto- cadherin Contactin L1CAM Neuroligin Postsynaptic Cadherin CNTNAP2