Progress in Identifying the Genetic Roots of Autism
Excerpts from the article printed in WSJ 9/24/2012 by
Melinda Beck
Scientists say that roughly 20% of autism cases can be
linked to known genetic abnormalities, and many more may be discovered. Pinpointing a genetic explanation can help
predict whether siblings are likely to have the disorder—and even point to new,
targeted treatments. Last week, for example, researchers reported that an
experimental drug, arbaclofen, reduced social withdrawal and challenging
behaviors in children and adults with Fragile X syndrome, the single most
common genetic cause of autism.
No single blood test or brain scan can diagnose autism
spectrum disorders—in part because environmental factors also play a major
role. But once a child is diagnosed, on the basis of symptoms and behavioral
tests, researchers can work backward looking for genetic causes.
Both the American Academy of Pediatrics and the American
College of Medical Genetics recommend that all children diagnosed with ASD be
tested for Fragile X Syndrome and other chromosome abnormalities. The newest
tests, called chromosomal microanalysis, can identify submicroscopic deletions
or duplications in DNA sequences known to be associated with autism. Together,
these tests find genetic explanations for more than 10% of autism cases.
Experts estimate that 400 to 1,000 individual genes may play
a role in the complex neurological issues involved in autism. Tests are
proliferating that look for mutations in some of those genes, thanks to new
technologies that let scientists sequence many genes at once.
Mount Sinai School of Medicine in New York City, for
example, is offering a new blood test that examines 30 different genes for
mutations known to be associated with autism or other developmental delays.
Some autism-related genetic disorders also carry a high risk
of cancer, seizures, heart disease or other health problems, so knowing about
them allows families and physicians to be vigilant for such issues.
Identifying genetic causes can also help families find
support groups, research programs and potential treatments tailored to their
child's specific needs. For example, one of the abnormalities Mount Sinai tests
for is the SHANK3 mutation on chromosome 22. It causes an autism-spectrum
disorder and Phelan-McDermid Syndrome, in which communication between nerve
cells is disrupted, impairing learning and memory. Researchers at Mount Sinai
found that an insulin-like growth factor could reverse that disruption in mice
and are now testing it in children aged 5 to 17 with SHANK3 mutations.
"Once you know the genetic cause of an intellectual
disability and understand the effect on the brain," says Alex Kolevzon,
clinical director of the Seaver Autism Center at Mount Sinai, "you can
start to think about targeted treatments."
If a genetic mutation is found, researchers can also test
the parents' DNA to see if the problem was inherited or if it occurred
spontaneously, in which case the risk of having another child with autism is no
greater than in the general population.
Another possible outcome: The test could find no abnormalities
in those 30 genes—or find "variations of unknown significance." That
would mean "we aren't certain what it means, but we may know more in the
future—and at least this will be in the patient's records," says Lisa
Edelmann, director of the genetic testing lab at Mount Sinai.
Several other academic medical centers offer their own
gene-sequencing tests for autism, looking at different suspect genes. The tests
typically cost about $2,000 and generally are covered by insurance. Other kinds of genetic tests may predict the
likelihood that a child will develop autism before a clinical diagnosis is
made.
Researchers at the University of Melbourne, Australia, have
developed a test that looks for 237 genetic markers called single-nucleotide
polymorphisms (SNPs). Some are thought to raise the risk of autism; others seem
to protect against it. The test correctly predicted autism with more than 70%
accuracy in people of Central European descent, but only 54% in those of
Chinese descent, according to a study in the journal Molecular Psychiatry this
month.
In April, IntegraGen Inc., a Cambridge,
Mass., biotech company, announced a test, called ARISk , that predicts the
likelihood that children aged 6 to 30 months who have older siblings with
autism will develop the disorder themselves. The company is also developing a
test to assess the risk of autism in children with no family history of the
condition.
The goal of such tests, says IntegraGen general manager Larry
Yost, is to have children at very high risk for autism referred to specialists
for a definitive diagnosis earlier. Studies show that early intervention can
significantly improve a child's IQ, language ability and social skills. But
many children aren't diagnosed until after age 4, according to the CDC.
Autism experts say the disorder should never be diagnosed
based on gene tests alone; some studies suggest that environmental factors may
play an equally important role.
The largest-ever study of twins with ASD—192 pairs—reported
last year that when one identical twin has autism, there is only a 70% chance
that the other twin will, despite their identical genetic makeup.
Among fraternal twins, the likelihood that a second twin
will have autism is 35%—nearly twice the risk other siblings face, the study
found. "That suggests there was something about their shared prenatal
environment that really increases the risk," says Clara Lajonchere, vice
president of clinical programs for Autism Speaks, a nonprofit science and
advocacy group.
Environmental factors—premature delivery, low birth weight,
maternal infections and maternal nutrition—have been implicated in autism, as
well as advanced parental age. Some experts suspect that the older the father,
the greater the chance for spontaneous genetic errors in sperm.
Most cases of autism probably involve some combination of
genetic and environmental factors, experts say, and research is burgeoning. More than 2,000 families with two or more
affected children have donated DNA samples to the Autism Genetic Resource
Exchange, funded by Autism Speaks, which makes the information available to
researchers around the world.
And the Autism Sequencing Consortium hopes to collect DNA
samples from 20,000 subjects for genome-wide association studies, and identify
100 more genes linked to autism in the next three years.
