Autism Consortium study in Pediatrics shows CMA finds more genetic abnormalities than current tests

The Autism Consortium, an innovative research, clinical and family collaboration dedicated to catalyzing research and enhancing clinical care for families with autism spectrum disorders (ASDs), announced today that the results of its comparison study of genetic testing methods for autism spectrum disorders is available from the journal Pediatrics through early online release in their eFirst pages today and will appear in the journal's April issue.

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, a collaboration between the Autism Consortium and Children's Hospital Boston, led by Consortium members Bai-Lin Wu, David Miller, Kira Dies, and Yiping Shen, 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.

“This is the largest study of clinical genetic testing for patients with autism spectrum disorders, and the results clearly show that chromosomal microarray analysis detects genetic abnormalities leading to ASD more often than a standard karyotype and fragile X testing,” said David Miller, MD, PhD, assistant director of the DNA Diagnostic Laboratory at Children's. “Chromosomal microarray was much better than a karyotype, but most clinical guidelines still recommend a karyotype and consider the microarray a second tier test.” Because of the dramatic increase in variations identified using CMA, the Autism Consortium recommends that CMA should be included in the first tier of diagnostic testing for children with ASD symptoms who have no clear genetic cause.

Genetic Testing Helps Families with Expectations, Securing Services

“This study demonstrates the importance of genetic testing for families and clinicians,” says Laurie Demmer, MD, Chief, Division of Genetics and Metabolism at the Floating Hospital for Children at Tufts Medical Center. “As we collect more data we will be able to determine the genetic causes of autism. More immediately though, these test results allow clinicians to confirm a genetic component for some families with children on the autism spectrum and even more importantly, gives families an end to the odyssey of trying to find a diagnosis for their child.”

There are many benefits for families to receive genetic testing:

Genetic test results can confirm a genetic component to a child's ASD and allow families to more quickly access services.
Using the test results clinicians can employ the experiences of other children who have the same condition. For example, providers are able to alert families to potential medical concerns that may have occurred in children with the same or similar diagnoses. Using new information for preventive surveillance, medical concerns can be addressed before symptoms even appear.

Finally, parents might be given a window into what to expect in their child's future. Working together, clinicians and researchers are sharing knowledge about what they are seeing as young children with ASDs pass through the developmental stages. They can pass this along to parents of similar children so that time can be used to prepare and address challenges, and advocate for a child's anticipated needs.

Genetic testing that identifies a specific cause for a patient's ASD diagnosis facilitates much more accurate genetic counseling about the chances that future children born to parents of a child with ASD would inherit the same genetic risk factor for ASD.

Findings Expand Knowledge Base for Autism Researchers

One of the Autism Consortium's most important objectives is spreading the word that in order to understand the causes of autism and develop new treatments, it is vitally important that families enroll in research.

“The Autism Consortium is extremely grateful to all of the families who have participated in our research studies,” said Deirdre Phillips, Executive Director. “We know that families are so busy dealing with their own day-to-day challenges and yet their participation adds to the pool of data and information needed to understand the causes of autism and to find effective treatments and therapies. The Autism Consortium encourages families to become vested partners in the research process, participating in studies whenever they can to provide the broadest possible foundation for new discoveries that will lead to new treatments.”

Autism genes have been difficult to identify because the disorder is complex, with a variety of causes stemming from many possible genes or combinations of genes. In addition, since people with autism tend not to have children, most of the genes identified thus far aren't inherited from a parent, but instead are mutated during embryonic development, making them hard to track through traditional genetic studies in families. Clinical genetic testing is adding to the body of knowledge that researchers are using to understand the genetics of autism.

About the Genetic Testing Methods Evaluated

Current genetic testing recommendations include fragile X testing and G-banded karyotyping to look for chromosomal abnormalities as first tier tests, which reveal changes in up to 3-5% of patients who do not have an obvious genetic condition such as Down syndrome.

Chromosomal Microarray Analysis (CMA), also called array comparative genomic hybridization (aCGH), is a molecular method for detecting genomic copy number changes, or deletions and duplications.

Whole genome CMA detects clinically significant copy number changes in at least 10% of patients with a variety of developmental problems such as developmental delay, mental retardation, and multiple congenital anomalies. Research studies for patients with ASD suggest a similar detection rate of about 10% using CMA, but the diagnostic yield in large clinical cohorts had not been well investigated prior to this study. This study presents data on clinical genetic testing of a large cohort of ASD patients by G-banded karyotyping, fragile X testing, and CMA.

About the Autism Consortium:

The Autism Consortium is a scientific and clinical collaboration that includes 14 institutions, supported by a non-profit that is dedicated to facilitating research and improving clinical care. The mission of the Autism Consortium is to catalyze rapid advances in understanding, diagnosis, and treatment of autism by engaging, supporting, and fostering collaboration among a community of clinicians, researchers, donors and families in order to improve the care of children and families affected by autism and other neurological disorders. The Consortium brings together the best minds from across the region from Beth Israel Deaconess Medical Center, Boston Medical Center, Boston University, Boston University School of Medicine, Broad Institute, Children's Hospital Boston, Harvard Medical School, Harvard University, Massachusetts Institute of Technology, Massachusetts General Hospital, the Lurie Family Autism Center at MGH for Children/LADDERS , McLean Hospital, The Floating Hospital for Children at Tufts Medical Center, UMASS Medical School, Worcester, and UMASS Memorial Health Care.