Boston, Mass. -- A large study from Children's Hospital Boston
and the Boston-based Autism Consortium finds that a genetic test
that samples the entire genome, known as chromosomal microarray
analysis, has about three times the detection rate for genetic
changes related to autism spectrum disorders (ASDs) than standard
tests. Publishing in the April issue of Pediatrics (and
online March 15), the authors urge that CMA become part of the
first-line genetic work-up for ASDs.
Expectant parents who have family members with ASDs, as well as
families who already have an affected child, often request genetic
testing. However, there is still only limited knowledge about
actual causative genes. The currently recommended tests
(karyotyping to look for chromosomal abnormalities and testing for
Fragile X, the single largest known genetic cause of ASDs) often
come up negative. Chromosomal microarray analysis (CMA) is a
genome-wide assay that examines the chromosomes for tiny,
sub-microscopic deletions or duplications of DNA sequences, known
as copy-number variants.
CMA offers about 100-fold greater resolution than standard
karyotyping. However, since it is new, it is often considered a
second-tier test. Depending on where a person lives, or what
insurance they have, CMA may not be covered by health insurance.
"Based on our findings, CMA should be considered as part of the
initial clinical diagnostic evaluation of patients with ASDs," says
Bai-Lin Wu, PhD, Director of Children's DNA Diagnostic Lab in the
Department of Laboratory Medicine, which has offered CMA to
families since 2006.
The research team, led by co-senior authors Wu (heading the
Children's team), and David Miller, MD, PhD, of Children's Division
of Genetics and Department of Laboratory Medicine (heading the
Autism Consortium team), assessed the diagnostic value of CMA in
the largest cohort to date -- 933 patients with a clinical
diagnosis of ASD (by DSM-IV-TR criteria) who received clinical
genetic testing in 2006, 2007 and 2008.
Half were Children's patients who had their samples submitted to
the hospital's DNA Diagnostic Laboratory, and the others were
recruited through the Autism Consortium, a research and clinical
collaboration of five Boston-area medical centers. Nearly half of
the patients were diagnosed with autistic disorder, nearly half
with PDD-NOS (pervasive developmental disorder – not
otherwise specified) and about 3 percent with Asperger disorder.
Ages ranged from 13 months to 22 years.
Testing included the two currently used tests (G-banded
karyotype and fragile X), as well as CMA. When the researchers
compared the tests' diagnostic yield, they found:
- Karyotyping yielded abnormal results in 2.23 percent of
patients
- Fragile X testing was abnormal in 0.46 percent
- CMA results were judged to be abnormal in 7.3 percent of
patients when the entire length of the chromosomes (the whole
genome) was sampled.
Extrapolating from these results, the researchers estimate that
without CMA, genetic diagnosis will be missed in at least 5 percent
of ASD cases. CMA performed best in certain subgroups, such as
girls with autistic disorder, and past studies indicate that it
also has a higher yield in patients with intellectual disability
(who constituted only 12 percent of this sample).
"CMA clearly detects more abnormalities than other genetic tests
that have been the standard of care for many years," says Miller.
"We're hoping this evidence will convince insurance companies to
cover this testing universally."
In all, roughly 15 percent of people with autism have a known
genetic cause. Establishing a clear genetic diagnosis helps
families obtain early intervention and services for autism, and
helps parents predict the possibility of having another child with
autism.
In addition, by pinpointing bits of chromosomes that are deleted
or duplicated, CMA can help researchers zero in on specific
causative genes within that stretch of DNA. They can also begin to
classify patients according to the type of deletion or duplication
they have, and try to find specific treatment approaches for each
sub-type of autism.
"Just in the last two years, a number of studies have revealed
the clinical importance of ever smaller chromosome deletions and
duplications found with advanced microarray technology," says Wu.
"These new, highly-efficient tests can help in the evaluation or
confirmation of autism spectrum disorders and other developmental
disorders, leading to early diagnosis and intervention and a
significantly improved developmental outcome."
Two known chromosome locations – on chromosome 16
(16p11.2) and chromosome 15 (15q13.2q13.3) accounted for 17 percent
of abnormal CMA findings. Both chromosome abnormalities were
initially linked with ASDs by Children's Hospital Boston and
collaborators in The New England Journal of Medicine and the
Journal of Medical Genetics, respectively, in 2008. Children's now
offers specific tests targeting both of these "hot spots."
However, the researchers note that most copy-number changes were
unique or identified in only a small number of patients, so their
implications need further study. Many of them are presumed to be
related to ASDs because they involve important genes, cover a large
region of the chromosome, or because the child is the first person
in that family to have the change.
"Some deletions and duplications are rare and specific to one
individual or one family," says Miller. "Learning about them is
going to be an evolving process. There won't be one single test
that finds all genetic changes related to autism, until we
completely understand the entire genome."
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