A Better Genetic Test for Autism

/PRNewswire/ -- 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."

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)

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Groundbreaking Research Begins for Pancreatic and Lung Cancers

/PRNewswire/ -- Georgia Tech and Saint Joseph's Hospital have joined together to begin the first regional research program to study the genetics and cell biology of pancreatic cancer. Tissue and serum samples from patients with cancer are being scrutinized to identify the differences in genetic and cellular features between normal and tumor cells. Findings from this research will be used for the ultimate purpose of developing tests for early diagnosis and identifying specific, targeted therapies to treat pancreatic cancer.

"The traditional treatment philosophy of 'one size fits all' is quickly becoming obsolete," says George Daneker, MD, the Medical Director of Oncology Research at Saint Joseph's Hospital and co-principal investigator of the study. "No two individuals are alike nor are two cancers; each is unique based on genetic and protein makeup."

Working with John McDonald, PhD, Chair of the School of Biology at Georgia Tech, and based on the research strategies from the acclaimed work of Dr. McDonald and Benedict Beningo, MD, with ovarian cancer patients, the current research is the first to focus on pancreatic cancer, accepted to be the most fatal of common cancers. Pancreatic cancer is similar to ovarian cancer in that it often goes undetected until the disease is too far advanced for curative therapy.

Dr. McDonald, recognized as a world authority in molecular genetics and genomics and Dr. Daneker, a surgical oncologist with an extensive background in basic and translational research, are applying state-of-the-art technologies toward identifying aberrant molecular and cellular mechanisms. Using microarray technology, gene expression patterns in pancreatic tumor tissue are compared with those present in the normal pancreas tissue. Microarray technology allows examination of more than 20,000 genes in a single experiment. Differences in the expression of genes encoding cellular proteins are of special interest with regard to the development of specific treatments.

There is also interest in the molecular basis of chemotherapy resistance. Some tumors respond very well to chemotherapy while others acquire resistance. By comparing the gene expression patterns in tumors that have become resistant to chemotherapy with patterns of these same tumors prior to chemotherapy, the research team hopes to identify the genes which mediate resistant. Identification of the mechanisms of resistance could lead to the development of treatment strategies that overcome the resistant pathways, making all tumors more responsive to treatment.

The research efforts will also focus on screening and early detection. By using a powerful analytical tool called mass spectrometry, coupled with data analysis using a "super-computer," the group hopes to identify patterns of molecular expression unique to cancer patients. This can lead to a sensitive screening test that only requires one drop of blood to run.

"Georgia Tech has the most advanced technology and the scientists who can help move these 'bench' research projects closer to 'bedside' treatments for patients at a very rapid rate," says Daneker. "Saint Joseph's brings the clinical expertise to take the treatments directly to the patient faster. It's a very unique partnership that facilitates rapid discovery and satisfies both our missions to bring the best treatments to patients in the quickest, safest way."

Saint Joseph's and Georgia Tech plan on expanding the collaborative research to lung cancers in April, as well as to prostate and colorectal cancers in the following months.

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