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!
Study relating to materials testing Detecting damages in non-magnetic steel through magnetism
23.07.2018 | Technische Universität Kaiserslautern
Innovative genetic tests for children with developmental disorders and epilepsy
11.07.2018 | Christian-Albrechts-Universität zu Kiel
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.
Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
14.08.2018 | Information Technology
14.08.2018 | Life Sciences
14.08.2018 | Life Sciences