Genetic Factors in Autism Spectrum Disorders

by Beth Rosen Sheidley, MS, CGC, Genetic Counselor, and Susan E. Folstein, MD, Director; New England Medical Center Autism Genetics Research Group

Since 1977, when the first autism twin study demonstrated higher concordance rates of autism among identical twins than fraternal twins, the evidence for inherited factors in autism spectrum disorders has gained widespread recognition among researchers. Based on several decades of work, scientists are now focusing in on specific chromosomal regions that are thought to contain autism-related genes, and are beginning to test candidate genes. The ultimate goal of this research, which is being carried out by researchers around the world, is to identify genes related to autism spectrum disorders, with the expectation that this information may lead to a better understanding of the disorders, their diagnosis, and their treatment. Although most of the genetic research to date has focused primarily on individuals with autistic disorder, researchers expect there to be considerable overlap in some inherited factors common to all autism spectrum disorders, including autistic disorder, Asperger syndrome and PDD/NOS.


In the first systematic and detailed autism twin study, the rate of concordance was compared between identical twins and fraternal twins. Concordance in this instance refers to the likelihood that if one twin has a diagnosis of autism, the second twin will also have a diagnosis of autism. Because identical twins share 100% of their genes, whereas fraternal twins share on average 50% of their genes, a higher concordance rate among identical twins is evidence for genetic influence. In the few twin studies carried out to date, the concordance rate for fraternal twins has been shown to be similar to the 5-8% recurrence rate observed among non-twin siblings. Concordance rates among identical twins are estimated to be approximately 60%, but have been reported to be as high as 95%. The fact that identical twins are not always concordant for autism indicates that there may be non-genetic factors that are important as well, but the high concordance rates are strong evidence for significant genetic influence. The results of family studies, which have shown increased rates of autism among siblings and close relatives, are also an indication of the role that inherited factors play in the development of autism. Although twin studies specifically focused on Asperger syndrome have not been carried out, it is apparent from family studies that Asperger syndrome occurs more frequently in siblings and other close relatives of individuals with Asperger syndrome, as well as siblings and close relatives of individuals with autism. Conversely, it also appears that autism occurs more frequently than would be expected among the close relatives of individuals with Asperger syndrome. Therefore the evidence from twin and family studies suggests that autism and Asperger syndrome cluster in the same families and are genetically related.


Evidence for an underlying genetic basis also comes from the many instances in which individuals with autism have been diagnosed with known genetic syndromes caused by changes in single genes or by chromosomal abnormalities. It is estimated that 10-15% of individuals with autism have an underlying medical or genetic diagnosis, such as fragile X syndrome, tuberous sclerosis, neurofibromatosis type 1 (NF1) and chromosomal abnormalities. Researchers at Duke University recently reported that some individuals with autism have mutations in the MECP2 gene, which is the gene related to Rett syndrome. In conjunction with the evidence from twin and family studies, the fact that a significant percentage of individuals with autism have an identifiable genetic condition supports the idea that inherited factors may lead to autistic characteristics. Although most published studies of the overlap between genetic syndromes and autism involve autistic disorders specifically, some do include individuals with Asperger syndrome and PDD/NOS as well.


In the majority of individuals with autism, there is as of yet no identifiable genetic cause. Based on all the evidence so far, researchers believe that autism is due to “complex” inheritance. Disorders that are due to complex inheritance do not follow the same predicted patterns of inheritance seen in single gene dominant, recessive, or X-linked disorders. It is possible that changes or “mutations” in several different genes must occur in combination with certain environmental triggers, such as exposure to certain substances in utero. This type of inheritance is often referred to as multifactorial because many different factors, genetic and/or environmental, are involved. It is estimated that as many as 15 different genes may be related to the occurrence of autism. It is possible that these genes may each have a small effect, in which case multiple gene mutations would be necessary for a child to develop autism. It is also possible that there may be several genes of major effect, but that the specific genes involved differ from family to family.

In order to determine the specific genes that may be involved, scientists perform what are referred to as “genome screens.” They use maps of the chromosomes (similar to road maps) in order to look for genes. Just as gas stations or restaurants can be used as landmarks when locating a friend's house, scientists use “markers” to find a gene. Markers are known regions or “sequences” of DNA along the chromosomes that may differ slightly from person to person or among populations. These differences, or “polymorphisms”, serve as landmarks that can be tested in individuals. In performing a genome screen, researchers look at many different markers throughout the genome, trying to find markers that are consistently found in family members who have a particular disorder, but not in family members without the disorder. These markers are landmarks that identify which chromosome a gene is located on (similar to which street a house is on). Statistical methods can tell a scientist how close these markers are to a gene. Testing additional markers will narrow the search area of the gene (similar to determining which block a friend's house is on). Markers that are very close to a gene are said to be “linked,” because the marker and the gene are almost always inherited together. Once scientists find a set of markers that are linked to a gene, then they say that they have found linkage. It is important to remember that linkage does not mean that a gene has been identified, but rather that the gene being searched for is somewhere nearby. There have been several published genome screens to date, and additional unpublished screens. Chromosomal regions of interest identified thus far include 2p, 4p, 6q, 7q, 13q, 15q, 19p, and Xq. Additional studies are underway to confirm linkage in these regions, and to narrow down the areas further.


Linkage results from genome screens tell us approximately where on a chromosome a gene is located. Researchers still need to determine the exact location of the gene (similar to finding a house on a particular street). One common method uses “candidate genes,” which are genes known through previous research to be localized to the region. A gene is called a candidate if its function relates in some way to the effect the disorder has on individuals who have the disorder. This laboratory technique is similar to knocking on the door of every house on a block until you find the one your friend lives in. Scientists test the candidate genes for mutations that might cause the disorder. If there are no mutations in the gene of a person who has the disorder, then that candidate gene could not have caused the disorder in that particular person. If all the candidate genes are tested and none are found to be responsible for the disorder, then the researcher studies genes whose functions are not yet known. Many genes may be tested until the correct gene is found. Then comes the long process of understanding how the gene works and why it causes the problems that it does. Recently a number of candidate genes have been under investigation. They include many genes that contribute to the development of the central nervous system.


Over the past decade many research groups around the world have worked independently to find genes related to autism spectrum disorders, but each group has been able to study only a small number of families. Recently, several of the groups joined together and obtained funding from the NIH to group all of the families together. By sharing data, and thus obtaining a much larger data set to work with, the researchers involved hope to speed the discovery of the genetic factors involved in autism.

A major focus of the work to identify genes now revolves around “subsetting” (grouping) families according to diagnosis and the presence of specific traits. For example, those families who have individuals with savant skills, obsessive compulsive tendencies, or spoken language delay may be considered in separate groups, the theory being that certain genetic factors involved may be related to those individual traits. Researchers have already identified a family with a severe speech and language disorder (not associated with autism) that is due to a single gene mutation. The family’s language problems are primarily related to the “structural” use of language, including grammar, syntax, and pronunciation of words, as opposed to language “pragmatics,” which refers to the social aspects of language, such as knowing when to take turns in a conversation. If it is the case that this and other structural language genes, along with other several other “pragmatic” language genes, are relevant to autism, and if there are genes specific to social aspects of development as well as repetitive/obsessive aspects of behavior (the other two areas affected in autism), then subsetting the families should make it easier to find the genes more quickly. The existence of genes that are related to traits, as opposed to specific diagnoses, would also explain why several different disorders often cluster in families. Researchers hypothesize that for autism to occur, an individual must inherit changes in genes that affect both social and structural language, social development and repetitive behaviors, whereas for Asperger syndrome inherited factors that impact structural language would not be involved.

Our hope is that over the next several years, with the funding from the NIH and a complementary effort just underway through the generosity of the National Alliance for Autism Research, researchers will identify the genes involved in autism spectrum disorders, and will begin to understand the biological mechanisms in a way that leads to better treatment. For updates on the latest research findings visit www.exploringautism.org, a website dedicated to keeping families informed about the genetics of autism.

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