From left: David Miller, MD, PhD, Bai-Lin Wu, PhD, and Yiping Shen, MD, PhD
Autism clearly has a genetic component, but specific genetic causes have been
hard to pinpoint. Now, the Genetics Diagnostic Laboratory at Children's has confirmed that a section of chromosome 16 (16p11.2) is deleted or duplicated in some people with autism spectrum disorders (ASDs). Findings were published online by The New England Journal of Medicine on January 9.
The defect accounts for an estimated 1 percent of autism cases, adding to the roughly 15 percent with known genetic causes, says study coauthor David Miller, MD, PhD, assistant director of the Genetics Diagnostic Laboratory. "I don't think we're going to find one cause that explains 50
percent of autism," Miller notes. "But
even if it's 1 percent at a time, we'll
eventually be able to figure out what's
going on in each particular family."
The defect was found through an extremely high-resolution whole-genome DNA analysis-the largest, most complete scan for ASDs to date. The Boston-wide Autism Consortium, of which Children's is a member, tested more than 3,000 DNA samples from a national repository. Of these, 1,441 were from people diagnosed with an ASD, and five had the chromosome 16 deletion.
Independently, a clinical diagnostic team at Children's, using an approach it designed for clinical use, found another five instances of the deletion among 512 patients referred for developmental delay and/or suspected ASDs. DeCODE Genetics in Iceland turned up another three cases.
"The ability to do extremely high-
resolution microarrays to look for very
small pieces of DNA is very new, but has direct and immediate application in
evaluating children for developmental delay and autism," notes Bai-Lin Wu, PhD,
director of the Genetics Diagnostic Laboratory and a senior author on the study.
Most of the deletions were de novo (not inherited), suggesting that the chances of another child in the family being affected are small, perhaps 5 percent rather than 50 percent for an inherited genetic defect.
The Children's team also identified four patients with a duplication of the chromosome 16 region, a seeming paradox that's not uncommon in genetics. "Genes may need to be expressed at exactly the right level within particular tissues," says Dr. Miller. "Either over-or under-expressing them can throw things out of balance within a cell, especially if they're interacting with other genes."
The missing/duplicated region contains some 25 genes whose function isn't yet known. The Children's researchers plan to study their patients more thoroughly to get further clues. "We don't yet know which of those genes is the critical one, or whether abnormalities in more than one of them are causing autism," says study coauthor Christopher Walsh, MD, PhD, Children's chief of Genetics and chair of the Consortium's advisory board.
Taking a different approach, Walsh's own lab has been studying large,
consanguineous Middle Eastern families that have multiple children with ASDs. Consanguineous families are often enriched for recessive genetic mutations, making them good subjects for study. Walsh's team is investigating several possible genetic associations; if confirmed, they will also be investigated in U.S. patients to see if any harbor mutations in the same genes.
Taking genetic findings to the clinic More about these new programs:
As genetic discoveries chip away at autism, Children's Hospital Boston is launching
clinics to treat and study patients with each sub-disorder. For example, Children's recently launched a clinic for Fragile X
syndrome, which accounts for some 2 to 6 percent of autism cases. The clinic will soon join a national clinical trial of a drug aimed at
correcting the underlying genetic and
biochemical abnormality in Fragile X-
excessive activity of mGLuR5, a brain
protein involved in learning and memory. A recent mouse study suggested that
blocking mGluR5 might help preserve brain function. A Children's team led by Jonathan Picker, MBChB, MSC, PhD, of the Division of Genetics, will recruit patients aged 12 and older and follow them closely with cognitive and behavioral measures.
Another planned trial, led by Omar Khwaja, MD, PhD in Neurology, will
test a novel drug in patients with Rett
syndrome, the leading single genetic
cause of autism in females. The compound may be important in early brain
development and myelination; in animal models, it improves symptoms and partly reverses underlying neuronal abnormalities.
"The more we understand the diverse causes of autism, the more we can fit the treatment to a child's specific condition," says Walsh. "We foresee additional special teams to treat each of the new conditions as we find them, so we can continue
translating new genetic discoveries into
better clinical care."
childrenshospital.org/fragilex and childrenshospital.org/rett.