Standards for Clinical Genetic Testing for Autism Spectrum Disorders

The goal of this project was to study the possible genetic causes of autism spectrum disorders and determine what types of clinical genetic tests should be offered to individuals with an ASD.  The study revealed that chromosomal microarray analysis (CMA) had the highest detection rate among clinically available genetic tests for patients with autism spectrum disorders and should be part of the initial diagnostic evaluation of all patients with ASDs unless a genetic diagnosis has already been made.

The study was a collaborative effort between the Autism Consortium and Children's Hospital Boston and was led by Consortium members Bai-Lin Wu, David Miller, Kira Dies, and Yiping Shen.  The research team examined 933 families (children and parents) who received clinical genetic testing for a diagnosis of Autism Spectrum Disorder (ASD) between January 2006 and December 2008.  The researchers compared the findings from three clinical genetic tests: G-banded karyotype and fragile X testing, the current standard battery of genetic testing, and chromosomal microarray analysis, for which testing guidelines have not yet been established. Chromosomal microarray analysis is similar to a karyotype, but can find much smaller chromosomal deletions and duplications.

The results showed that chromosomal microarray analysis identified more genetic abnormalities associated with autism than the standard testing methods combined:

• Standard testing method G-banded karyotype testing yielded abnormal results in 19/852 patients (2.23%)
• Standard testing method Fragile X testing results were abnormal in 4/861 patients (0.46%)
• In contrast, chromosomal microarray analysis (CMA) identified deletions or duplications in 154/848 (18.2%) patients and 59/848 (7.0%) were clearly abnormal. 
• As a result, chromosomal microarray was better than a karyotype for all but a small number of patients with balanced rearrangements, and those were not necessarily a cause of ASD.

To read this paper go here.

Genome-Wide Scan Identifies New Genes Associated with Autism

Although no one knows for sure what causes the various manifestations of Autism Spectrum Disorders, scientists agree that gene abnormalities are associated with most cases of the condition. To help elucidate genes involved in ASDs, Autism Consortium researchers collaborated on a genome-wide scan.

The Autism Consortium Genome Scan was completed in October 2007 using data made available by the Autism Genome Research Exchange (AGRE), a program of Autism Speaks.  The Autism Consortium researchers scanned genetic data from more than 3,000 individuals of which 1,441 were diagnosed with an ASD, in order to identify genes that appeared to be associated with ASDs.  The research team took advantage of a new gene scanning technology from Affymetrix, using its new 5.0 chip, and wrote two different but complementary computer algorithms to identify the genetic variation.

The researchers identified a region on chromosome 16 that appears to play an important role in susceptibility for ASDs. In the majority of cases the deletion was de novo, a newly occurring change in the DNA that the affected individual did not directly inherit from either parent. The authors verified the clinical importance of their findings through independent observations in the Genetics Diagnostics Laboratory at Children's Hospital Boston, a member of the Autism Consortium, and at deCODE Genetics Inc. in Iceland.  The research team was led by Mark J. Daly, PhD, an Autism Consortium member at the Center for Human Genetic Research and the Department of Medicine at Massachusetts General Hospital; he is also a senior associate member of the Broad Institute of the Massachusetts Institute of Technology and Harvard.

Analysis by the Autism Consortium team identified five individuals who had the de novo deletion out of 1,441 with ASDs in the AGRE database.  Researchers at Children's Hospital Boston, found an additional five cases of the deletion in clinical genetic testing of 512 patients referred for developmental delay and/or suspected ASDs.  An additional independent observation by deCODE genetics demonstrated three individuals out of 299 on the autism spectrum had the identical deletion, bringing the total in this three-institution study to 13 patients with the same deletion. Equally striking are the findings of gene duplications in the same region among the patients studied. Seven individuals in the AGRE database and four individuals from Children's Hospital had extra copies of genes on chromosome 16 in a region matching the area where others had missing or deleted genes.

Many significant advances in biomedical science depend on new technology that enables researchers to answer questions that previously could not be answered. The ability to sequence the human genome by using a combination of computer power and automated instruments that read DNA to reveal the identity and physical location of genes or gene deletions is crucial to unraveling the genetics of autism, just as it was the key technology that enabled scientists to sequence the entire human genome. The autism genome can be thought of as a subset of the human genome. Each cell in our bodies (and we have a trillion cells) contains a complete genome. But each cell is programmed to use some of its genes and not others. It is the genes that contribute to susceptibility to ASDs that constitute the Autism Genome.  At the present time, there are a number of genes associated with ASDs on the list. As science advances, some may be removed, if it is determined that they are not related to ASDs after all; others may be added. The recent studies by Autism Consortium scientists on gene deletions and duplications on chromosome 16 are an extremely important addition to the Autism Genome list because they occur in such a large percentage of individuals with ASDs.

This research was published in the New England Journal of Medicine and the paper can be accessed here.