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Feb. 7, 2003 — Editor's Note: Researchers have identified at least one gene that may be responsible for autism, according to a report in the March issue of the American Journal of Human Genetics. Using a new statistical method combined with careful observational classification, investigators have determined that a gene on chromosome 15 coding for the gamma-aminobutyric acid (GABA) receptor beta3-subunit (GABRB3) is involved in a distinctive autistic symptom of "insistence on sameness" (IS).

Autistic children with IS exhibit repetitive compulsions and extreme resistance to even trivial changes in their daily routine. The statistical technique of ordered subset analysis revealed that those families whose children had high scores in the IS category had a strong link to the GABRB3 gene on chromosome 15q. Rather than lumping all autistic children together for the purposes of analysis, separating them into clinically meaningful subgroups allowed validation of this genetic link.

To determine the potential of this discovery, Medscape's Laurie Barclay interviewed the lead investigator of the study, Margaret A. Pericak-Vance, PhD, director of the Duke Center for Human Genetics and a professor and chief of medical genetics at Duke University Medical Center in Durham, North Carolina.

Medscape: In simplified terms, how does this new statistical method work, and how does it facilitate genetic analysis?

Dr. Pericak-Vance: First, we identify families with two or more affected siblings. The statistical technique allows us to quantitate similarities between families across a number of different variables. We distinguish single traits, look for genetic similarities for each trait, and use the statistical method to pull them together. If we can identify a group of patients with similar characteristics, that enhances our ability to determine which gene is responsible. What's nice about this is that we can test the statistical significance of the link, so it's not just a fishing expedition.

Now that we've done all the sophisticated genome technology and we've looked at thousands of markers, we have to apply this technology to clinical problems like diabetes, cardiovascular disease, and dementia. But we haven't yet exploited all the clinical information. In the past, we thought that you either have a disease like diabetes or you don't, but that's too simplistic. None of these complex diseases is just a single condition — each of the subgroups is different clinically and most likely genetically. The clinical subgroups help define the genetics.

Medscape: Have you applied this method to other genetic diseases yet?

Dr. Pericak-Vance: Any quantitative trait in any inherited disease can be evaluated for its genetic significance. We've looked at age of onset as a marker in familial Alzheimer's disease. We found a nucleus of families with early onset and have subjected them to this type of factor analysis, and that work is now in press.

Medscape: What is the function of the gene linked to "insistence on sameness?"

Dr. Pericak-Vance: As you would suspect from a gene coding for a GABA receptor, it is probably involved in neurotransmission, but it's too early to know exactly how. So far we've found a cluster of genes in the same region of chromosome 15 as GABRB3, and they all are somehow involved with GABA. For example, one codes for the alpha-subunit. Autism is a very complex condition, so we'll be looking at how all three genes interact to affect clinical presentation.

Medscape: Is the GABRB3 gene also implicated in other neuropsychiatric disorders?

Dr. Pericak-Vance: Genetic links to Angelman syndrome and Prader-Willi syndrome are also clustered in the same region as GABRB3. Some children with these genetic disorders also have autistic-like symptoms, especially repetitive behavior.

Medscape: Do you suspect that other genes identifed as being related to autism or to other neurobehavioral disorders will also involve GABA or other neurotransmitters?

Dr. Pericak-Vance: Possibly. We're looking at other areas and other chromosomes. Five or six groups around the world have also been looking at other genetic markers. Although autism is a complex disease with a variety of symptoms, there has been reasonably good concordance in genetic findings around the world. Chromosomes 7 and 2 may be involved in different clinical aspects of autism. But the function of these implicated genes is still unknown.

Everyone is madly testing candidate genes — it's a wide-open area. It sounds like we're only taking baby steps, but every little step helps. It's like we're stripping away tiny pieces of orange peel and eventually the whole fruit will come into view. Finding even a single gene marker leads to exponential progress, as it gives us a clue as to the mechanism.

Medscape: What are the other distinctive features in autism that could help define subgroups, and are these subgroups also being analyzed genetically?

Dr. Pericak-Vance: A group at Mt. Sinai Hospital in New York has linked phrase speech delay to chromosome 2, and we've confirmed that those children in whom ability to speak in phrases is delayed beyond 36 months of age have a distinctive genetic marker on chromosome 2.

Medscape: Do the findings of this study suggest that heredity is more important than environment in autism, or do these findings still allow for interactions between genetic predisposition and environmental factors?

Dr. Pericak-Vance: It's difficult to look at either heredity or environment in isolation. If there is a genetic predisposition interacting with environmental factors, we need to know the responsible gene or genes before we can pinpoint which environmental risks are involved. It's quite possible that subgroups differing genetically may each be susceptible to different environmental risk factors.

Medscape: Ultimately, will identification of these genes lead to development of new treatments?

Dr. Pericak-Vance: Eventually. We may find a gene that is not a good target, but it may lead us into a pathway that does provide a good target for therapeutic intervention.

Am J Hum Genet. 2003;72(3):000. Published online Feb. 3, 2003

Reviewed by Gary D. Vogin, MD

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Laurie Barclay, MD is a staff writer with WebMD. Medscape Medical News is edited by Deborah Flapan, a news coordinator at Medscape. Send press releases and comments to news@webmd.net.   Medscape Medical News 2003. © 2003 Medscape

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