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Novel chromosome abnormality appears
to increase risk of autism
Study takes first look at
extent of institutional relationships and potential consequences
BOSTON - January 9, 2008 - A multi-institutional study involving
Massachusetts General Hospital (MGH) researchers has identified
a chromosomal abnormality that appears to increase susceptibility
to autism. In a New England Journal of Medicine report that
is receiving early online release, the investigators - most of whom
are associated with the Boston-based Autism
Consortium - report that a segment of chromosome 16 is either
missing or duplicated in about 1 percent of individuals with autism
or related disorders, a frequency that is comparable to other genetic
syndromes associated with the disorder.
"While epidemiologic studies indicate a very large genetic
component to autism, little is known about how specific genes are
involved," says Mark Daly, PhD, of MGH
Center for Human Genetic Research, the study's senior author
for gene discovery. "We're still a long way from understanding
how this chromosomal deletion or duplication increases the risk
for autism, but this is a critical first step toward that knowledge."
Population studies indicate that up to 90 percent of cases of autism
and what are referred to as autism spectrum disorders have some
genetic component, but only 10 percent of cases can be attributed
to known genetic and chromosomal syndromes. Since several of those
conditions involve deletions or duplications of chromosomal segments
- including an inherited deletion of a region of chromosome 15 -
the investigators conducted a complete genome scan of samples from
the Autism Genome Research Exchange, which contains DNA from families
in which at least one child has autism or a related disorder.
The scan of more than 1,400 affected individuals and a similar number
of their unaffected parents revealed that an identical region of
chromosome 16 was deleted in 5 individuals with an autism spectrum
disorder but not in any of the parents, implying that the deletion
had occurred spontaneously and was not inherited. To confirm this
observation, clinical testing data from almost 1,000 patients from
Children's
Hospital Boston - about half of whom had been diagnosed with
autism or a related developmental delay - was evaluated. Among those
with a developmental disorder, 5 children had the same deletion,
and in another 4 the chromosome segment was duplicated. Again, no
abnormalities were seen in DNA from children without autism or developmental
delay.
Confirmatory data was also obtained by colleagues from deCODE Genetics
of Iceland, who found the same deletion in 3 of almost 300 individuals
with an autism spectrum disorder and also in a few with other psychiatric
or language disorders. Among almost 20,000 members of the deCODE
database who had not been evaluated for language or psychiatric
disorders, the deletion was seen in only 2 individuals. Results
from the deCODE scan indicate that, while this chromosomal deletion
occurs in only .01 percent of the general population, it is 100
times more prevalent in those with autism spectrum disorders.
"These large, non-inherited chromosomal deletions are extremely
rare," says Daly, "so finding precisely the same deletion
in such a significant proportion of patients suggests that it is
a very strong risk factor for autism. We're now pursuing more detailed
genetic studies to figure out which genes in this region are responsible
for this effect in order to gain a better understanding of the underlying
biology and potential clues to therapeutic approaches."
A member of the Autism Consortium, which includes 14 Boston-area
institutions, Daly adds, "The ability to rapidly and seamlessly
translate research findings to the evaluation of patients under
clinical care - providing families with information that can help
them understand their child's condition and assess potential risks
to other children - relied on the integrated community of researchers
and clinicians made possible through the Autism Consortium."
Daly is an assistant professor of Medicine at Harvard Medical School
and a member of the Broad Institute of Harvard and Massachusetts
Institute of Technology.
Bai-Lin Wu, PhD, director of the Genetics Diagnostic Laboratory
at Children's Hospital Boston is the senior author for clinical
genetics of the NEJM report. Other MGH co-authors are lead
author Lauren A. Weiss, PhD, Yiping Shen, PhD, Joshua M. Korn, Manuel
Ferreira, PhD, Todd Green, Douglas Ruderfer, David Altshuler, MD,
PhD, Rudolph Tanzi, PhD, Susan L. Santangelo, ScD, James Gusella,
PhD, and Pamela Sklar, MD, PhD. Co-authors at Children's Hospital
are David Miller, MD, PhD, assistant director of the Genetics Diagnostic
Laboratory; Orah Platt, MD, and Christopher Walsh, MD, PhD. Additional
co-authors are Dan Arking, PhD, and Aravinda Chakravarti, PhD, Johns
Hopkins University; Ragnheidur Fossdal, Hreinn Stefansson, PhD,
and Kari Stefansson, MD, PhD, deCODE Genetics; and Evald Saemundsen,
State Diagnostic and Counseling Center, Iceland. The study was supported
by grants from the Autism Consortium, a Ruth Kirschstein National
Research Service Award, the National Health and Medical Research
Council of Australia, the Ellison Foundation, the Simons Foundation
and the National Institute of Mental Health.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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