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:
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."
The paper's co-first authors were Autism Consortium members Yiping Shen, PhD, of Children's Department of Laboratory Medicine and the Center for Human Genetic Research at Massachusetts General Hospital, and Kira Dies, ScM, LGC, of the Family Research Network of the Autism Consortium and Children's Multi-Disciplinary Tuberous Sclerosis Program. A number of specialists from Children's Departments of Neurology, Developmental Medicine and Clinical Genetics and physicians from other medical centers in greater Boston were also authors on the study. The research was supported by the Nancy Lurie Marks Family Foundation, the Simons Foundation, Autism Speaks and the National Institutes of Health.
Families interested in scheduling an appointment at Children's may call the Developmental Medicine Center (617-355-7025) or the Department of Neurology (617-355-2711).
Citation: Shen Y; et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 2010 Apr; 125(4):e1-e17. (Published online March 15)
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 13 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.
Keri Stedman | EurekAlert!
Diagnoses: When Are Several Opinions Better Than One?
19.07.2016 | Max-Planck-Institut für Bildungsforschung
High in calories and low in nutrients when adolescents share pictures of food online
07.04.2016 | University of Gothenburg
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
25.10.2016 | Earth Sciences
25.10.2016 | Power and Electrical Engineering
25.10.2016 | Process Engineering