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09 March 2007
Researchers Explore Link between Genetic Deletion and Autism
Emory researchers are exploring how a disorder associated with a missing portion of chromosome 22, known as the 22q11 deletion syndrome (22q11DS), may be related to autism spectrum disorders. The research study is the first of its kind using a combination of evaluations representing the gold standard of comprehensive diagnostic tests for autism. Understanding the link between this genetic deletion and autism spectrum disorders promises to facilitate earlier diagnosis and therefore more effective treatment of these kinds of cognitive disorders.

"Early treatment is everything," says Joseph Cubells, MD, PhD, associate professor of human genetics and psychiatry and behavioral sciences at Emory University School of Medicine, and lead investigator of the study. Early pharmacological and behavioral interventions are important because a child's behavior affects his social environment, which, in turn, feeds back onto the child, says Dr. Cubells. "A fundamental property of the brain is that it constantly remodels itself in response to experience. What initially may be a manageable psychiatric or physical problem can eventually become much worse if it is not treated early," he says.

Those with autism spectrum disorders may have impairments in social, communicative and behavior development often accompanied by abnormalities in cognitive functioning, learning, attention and sensory processing.

Cubells and his colleagues tested only those individuals known through molecular testing to have the 22q11DS. The researchers invited each to participate in the study regardless of their medical or psychiatric history. By contrast, some studies recruit subjects through psychiatric clinics or advertisements, both of which include more severely impaired individuals, thus biasing study samples.

The researchers are using both the highly accurate parent interview test--the Autism Diagnostic Interview-Revised (ADI-R)--and the child observation measure--the Autism Diagnostic Observation Schedule (ADOS)--to determine whether a child meets criteria for a diagnosis of autism and thus test whether the 22q11 deletion may alter risk for the disorder, says Kimberly Rockers, MEd, diagnostician and manager of the study. "Having such a thorough battery of tests will increase the accuracy of assessment," she says.

The ADI-R includes an interview with a patient's caretaker to assess developmental history and day-to-day behavior concerning language and communication, social interactions and repetitive behaviors and interests. The ADOS focuses on social interaction, verbal and nonverbal communication, play and the creative use of materials.

Although this is the first study to include the ADOS, says Rockers, previous research has shown that up to 50 percent of individuals with 22q11DS may be considered autistic, at least in the broadest sense of the term. Autism has an incidence rate of 1 in every 150 children in the general population, according to the Centers for Disease Control and Prevention (CDC). Symptoms include varying degrees of impairment in communication, language, social skills and repetitive patterns of behavior, although the severity of the impairments varies widely.

The 22q11DS appears to elevate a patient's risk for developing schizophrenia, a severe mental disorder that usually has its symptomatic onset in late adolescence or early adulthood. The researchers initiated the study of 22q11DS to investigate the deletion's association with schizophrenia. Dr. Cubells and his co-investigators were looking to better classify behavioral, neuropsychological and genetic risk factors for schizophrenia for patients known to have the deletion. It was during these studies that the researchers noticed an overlap between the 22q11DS and autism.

Although some with the deletion may never exhibit any severe physical or mental disorders related to 22q11DS, those who do often exhibit a wide range of disorders including attention deficit hyperact ivity disorder (ADHD); cardiac, renal, immunological and endocrine disorders; cleft palate; speech difficulties and dental problems. "It's hard to name an organ system that it doesn't affect," says Dr. Cubells.

Thus, says Rockers, it is critical for those with the deletion who are diagnosed with autism or schizophrenia to undergo a thorough physical workup. "These are classical disorders where the need for subspecialists such as cardiologists, dentists, immunologists and even speech and language pathologists, may be needed. It takes a very knowledgeable work up, but it takes a very humble work up. It is especially important for a psychiatrist to recognize that based on the medical complexity and the social problems at home and at school, the doctor may not be able to write a prescription that takes care of everything," says Rockers.

To address the need for comprehensive multi-disciplinary evaluation and treatment of the medical and behavioral difficulties encountered by patients with 22q11DS, Emory School of Medicine recently teamed with Children's Healthcare of Atlanta to establish the Southeast Regional Center of Excellence for 22q. The center includes specialists in cardiology, immunology, gastroenterology, dentistry and orthodontics, speech pathology, clinical genetics as well as several other consulting specialties (including Dr. Cubells and his colleagues in psychiatry). With locations at both the Emory Children's Center and the Center for Craniofacial Disorders at Children's at Scottish Rite, the center streamlines the process of clinical visits for patient families, provides comprehensive family and provider education, and conducts research to advance diagnosis and treatment.

Cubells says he and his collaborators will continue their work on 22q11DS by comparing autistic features in patients known to have the deletion with autistic features in patients known to have other chromosomal disorders that have a high rate of autism, such as fragile X syndrome. Fragile X syndrome is the most common inherited cause of mental retardation. "Such comparative studies--if they reveal systematic differences in behavioral phenotypes--should help us home in on the relationship between specific genes and certain behaviors," he says.

Dr. Cubells and Rockers' collaborators include co-investigator Opal Ousley, PhD, Emory assistant professor of psychiatry and behavioral sciences; Elaine Walker, PhD, Dobbs professor and chair of psychology in Emory College; Karlene Coleman, RN, MN, genetics counselor at Children's Healthcare of Atlanta and Emory University Department of Human Genetics; Lisa Kobrynski, MD, MPH, Emory assistant professor of pediatrics; and Michael Zwick, PhD, Emory assistant professor of human genetics. Dr. Zwick is using microarray-based resequencing--a new technology he helped develop--to search for genes on targeted sections of the X chromosome that could be related to the development of autism.

This study was funded by the Robert W. Woodruff Health Sciences Center Fund, as part of Emory's Predictive Health Initiative. For more information on the 22q11DS, please visit

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