Genetics and autism: a briefing

The exact causes of autism are unknown, but it is thought that genetics may play a role, along with other factors such as environmental ones. This section will tell you more about the research that has been carried out in the field of genetics and autism.

A brief note on genetic terminology

The human genome is arranged into 23 pairs of chromosomes, numbered 1-22, with sex determining chromosomes being designated X and Y. Humans have between 30,000 and 40,000 protein-encoding genes which control all aspects of our development, from birth to death, including our growth, stature and appearance. They also combine in complex ways that play critical roles in determining our intelligence, personality and other broad characteristics.

DNA, deoxyribonucleic acid, is the true chemical of life. It is the essential component from which our genes are made. It directs the different types of cells that make up the human body. We have a hundred million million cells so it is very much, as Watson described, a golden molecule. All these cells contain the inherited information that comes from the first, single cell at fertilization. These instructions carry all the biological details necessary for making all the different tissues and organs, and the cells of blood, skin, kidneys, lungs and many others including, of course, the brain. These guidelines make us each unique, apart from identical twins who share the same genetic make-up.

As the embryo and then the child matures, the DNA script within its cells is read and translated into proteins from which tissue, nerve cells and hormones are constructed. These in turn are transformed into organs, thought processes, memories and even behaviour patterns, which range from instinctive flinch reactions to complex tendencies including elusive musical talents, and the urge to use our left or right hands (Ridley 2000).

We now know far more about genetic mechanisms and know the position and structure of several hundred genes which cause inherited diseases. It is good that these simple inherited ailments, each caused by single mutated genes, are now being brought under control. Scientists are now busy with the more intractable problems, one of which is autism.

What causes autism?

In 1943 Leo Kanner, who originally described autism, identified the key features of the condition, which include impairments in social interaction and communication skills, coupled with unusual interest patterns and stereotyped behaviours. He suggested that autism was an inborn defect, as he observed that symptoms were often present from a very young age (Kanner 1943). Since then research has found that occasionally a few specific medical conditions may give rise to autism (Rutter et al 1994; Barton and Volkmar 1998). These include genetic disorders such as tuberous sclerosis, fragile X syndrome and phenylketonuria. However, in the vast majority of cases no single identifiable medical disorder can be found to explain the autism. Nevertheless, it is clear that in children with these idiopathic (unknown cause) forms of autism, markers of abnormality in brain development, such as an abnormally large head/brain and an increased risk of epilepsy are frequently present.

The precise nature of the brain abnormality still remains elusive, despite considerable research effort. For many years it was felt that there was unlikely be a genetic basis for autism, because most families only have one child with the condition (Pauls 1987). Over the past two decades, however, systematic family and twin studies have shown that genetic factors play a crucially important role in causing apparently idiopathic forms of the condition (Lamb et al 2000).

This conclusion is supported by the fact that that about 3% of siblings of a child with autism also develop autism (Piven and Folstein 1994). At first sight this may appear to be a small number and well below the 25-50% rate of disorder usually observed in siblings of children with single gene conditions like cystic fibrosis or muscular dystrophy. However, although the absolute rate is low, it is still 50 to 100 times greater than the rate in the general population. It should be noted that the sibling rate of 3% is different from the true recurrence risk, which is thought to be higher. This is because the prevalence calculation simply counts the number of siblings with autism, and does not allow for stoppage (the phenomenon whereby parents with a child with severe learning disabilities choose not to have further children).

Following the realisation that autism runs in families, researchers went on to determine whether this familial tendency was due to genetic or environmental factors (Bolton et al 1994). To answer this question they compared the rates of autism in identical and non-identical co-twins of twins with autism and found that the identical co-twins were much more likely to develop autism than were the non-identical co-twins. As the main difference between identical and non-identical twins lies in their genetic similarity (identical twins are identical genetically, whereas non-identical twins only share about half their genes), the results of the studies clearly showed that genetic factors play an important role in causing autism. In fact, the twin concordance rate (the proportion of twins who both have autism) in identical twin pairs (around 60%) was very much higher than the concordance rate in non-identical twin pairs. The substantial difference in the magnitude of the concordance rates, in addition to other findings, suggests that autism is a complex genetic disorder, probably entailing the combined action of several susceptibility genes (Turner, Barnby and Bailey 2000).

A useful overview of what is known about the genetics of autism can be found on the National Library of Medicines OMIM site (McKusick 2001).

Gene hunting

Over the last decade, staggering and revolutionary advances in the methods of genetic investigation have made it possible to hunt for genetic abnormalities and susceptibility genes, searching through the entire human genome systematically. Several groups have now embarked on a hunt for the genes that create a susceptibility for autism, by undertaking genome searches. Exciting and promising new leads are beginning to emerge from these studies. For example, an International Molecular Genetic Study of Autism Consortium (with genotyping done at the Wellcome Trust Centre for Human Genetics in Oxford) was the first to identify the location of three or four susceptibility genes that might possibly be involved in the causation of autism (International Molecular Study of Autism Consortium 1998).

Other groups have subsequently reported results from their studies and some consensus is beginning to emerge as to where some of the genes might be located (Risch et al 1999; Turner, Barnby and Bailey 2000). As always there are many blind alleys where it turns out that initially promising results are found not to hold up to scrutiny. Moreover, following confirmation of the location of a possible susceptibility gene, there is still much work that has to be done to pinpoint the genes.

The next step in the research effort is to test many more families in order to map the exact location of the susceptibility genes more precisely. It will then be necessary to check all the genes at each location for mutations or other functionally meaningful variations that might give rise to the abnormal brain development underlying autism. Automated procedures for doing the laboratory tests mean that the genotyping required in such studies can be done far faster than ever dreamed of just 10 years ago. In fact, the main rate-limiting step to these studies nowadays is the recruitment and assessment of the children with autism and their families. This is because the most informative families for this type of study are rare and hard to identify, so the search often entails international collaboration. Also, the careful, medical, behavioural and psychological assessments that are required are labour intensive and time consuming. They also entail considerable clinical skill and experience and few people have the necessary training.

Another challenge concerns the possibility that there are a number of different causes of autism. We already know that several different medical conditions occasionally cause the condition, so we expect that there may be several different types of autism, although as yet we do not know how many or what causes them. There is some evidence to suggest that features like the absence of speech or the presence of an unusually small head may signify different subtypes, but this needs to be confirmed. Quite how many subtypes will be identified remains open to question.

A further unresolved puzzle concerns the fact that far more boys than girls develop autism. Two main explanations are being explored. The first is that there may be a gene on the X chromosome that modifies the risk of developing autism (Skuse 2000). The fact that girls possess two X-chromosomes (one inherited from the mother and the other from the father) whereas boys have just one  (inherited from the mother) has led to speculations about X linked genes causing autism. As yet however, there is very little direct evidence to support these theories. An alternative explanation is that sex hormone differences between boys and girls, rather than genetic differences, are responsible for the lower rate of autism (Lord and Schopler 1987). Again, however, there is no direct evidence to support this explanation.

What is inherited?

Another major finding from the twin and family studies is that the genetic influences involved in creating a susceptibility to autism, also carry a risk for the inheritance of more broadly defined forms of autism spectrum disorder, as well as more subtle abnormalities in the development of social communication skills (Hughes, Plumet and Leboyer 1999). For example, the UK twin and family studies showed that close relatives of children with autism were at higher risk not only for developing autism, but also for inheriting variants or partial forms of classic autism including quite subtle difficulties in communicating and establishing friendships or love relationships (Bailey et al 1995). Although clinically significant, these subtler problems fell well short of the required criteria for a diagnosis of autism. Importantly, the twin data indicated that even the subtle impairments were partly genetically inherited. Certain personality attributes such as being socially retiring or withdrawn in nature also seem to run in the families of people with autism, although there is more uncertainty about this. Future research will need to confirm whether this really is the case and clarify whether these personality attributes also stem from the genetic liability to autism.

One of the challenges here is to tease apart the extent to which strengths and difficulties stem from the inherited genetic liability to autism or instead from the demands of raising a handicapped child. This is particularly so with regard to symptoms of anxiety and depression, as these also seem to occur in relatives of people with autism more commonly than expected. Recent evidence suggests that the symptoms of anxiety and depression do not go hand in hand with the social communication impairments that are linked to autism. It appears instead that some other explanation will have to be found (Piven and Palmer 1999).

What about the environment?

Genes never work in isolation they always interact with environmental factors in determining how people grow and develop. Similarly, when genes develop a fault the consequences depend in part on other genetic and environmental factors. A good example of this is provided by a genetic condition called phenylketonuria. In this disorder, mutations in the enzymes that break down the naturally occurring chemical phenylalanine lead to its build up in the brain. High doses of phenylalanine damage brain development and lead to learning difficulties. However, elimination of phenylalanine from the diet stops the harmful build up of the chemical in the brain and, hence, prevents the brain damage and learning difficulties developing.

As yet, research in autism has failed to identify any major environmental factor that contributes to causation. For some time it was thought that pregnancy and birth complications, which have been linked to autism, may be an environmental trigger for autism or a factor that determines severity. However, recent research has cast doubt on their significance, partly because the complications tend to be comparatively mild and not the kind that ordinarily result in brain damage (Deb et al 1997). Why then should children with autism be more likely to experience mild problems during pregnancy and birth? One possible explanation comes from studies of children with genetic conditions such as Down's syndrome. Children with Down's syndrome are also prone to pregnancy and birth complications, partly because their mothers tend to be older but perhaps also because whilst in the womb their abnormal development interferes with the maintenance of normal pregnancy. Research has suggested that similar mechanisms may give rise to the pregnancy and birth complications associated with autism (Rutter et al 1993).

Future research will need to continue searching for possible environmental causes. In addition, more research will be needed to determine what factors lead to pairs of identical twins having very different forms of manifestation. Environmental or chance factors must be operating.

Treatment

Although there are effective treatments for ameliorating autism, there are no cures available and the benefits of treatment tend to be modest. One of the major goals of genetic research is to improve our understanding of what goes wrong in brain development so that new more effective and better targeted treatments can be developed. For instance, if a faulty gene is identified, pharmaceutical companies have a target and may try to develop a designer protein or a medication that will affect gene expression, by turning a gene on or off, or speeding up or slowing down its action. Another possible approach is gene therapy put simply replacing the bad gene with a new, good one. Many argue that this approach is needlessly complex and unlikely to play a major role in the treatment of autism.

Conclusion

Autism has been shown to be strongly genetically determined and research in this area is providing important new leads. Further genetic investigations should be highly rewarding not only in identifying susceptibility genes, but also in helping clarify the role of environmental factors.

Bibliography

Lamb, J. A. et al (2000) Autism: recent molecular genetic advances. Human Molecular Genetics, 9, pp. 861-868.

Rutter, M. (2000) Genetic studies of autism: from the 1970s into the millennium. Journal of Abnormal Child Psychology, 28, pp. 3-14.

Tanguay, P. (2000) Pervasive Developmental Disorder: a 10-year review. Journal of the American Academy of Child & Adolescent Psychiatry, 39, pp.1079-1095.
Available from the NAS Information Centre

References

Bailey, A. et al (1995) Autism as a strongly genetic disorder : evidence from a British twin study. Psychological Medicine, 25, pp. 63-77.

Barton, M. and Volkmar, F. (1998)  How commonly are known medical conditions associated with autism? Journal of Autism and Developmental Disorders, 28(4), pp. 273-278.
Available from the NAS Information Centre

Bolton, P. et al (1994) A case-control family history study of autism. Journal of Child Psychology and Psychiatry, 35(5), pp. 877-900.
Available from the NAS Information Centre

Deb, S. et al (1997) A comparison of obstetric and neonatal complications between children with autistic disorder and their siblings. Journal of Intellectual Disability Research, 41(1), pp. 81-86.

Hughes, C., Plumet, M.-H., and Leboyer, M. (1999) Towards a cognitive phenotype for autism: increased prevalence of executive dysfunction and superior spatial span amongst siblings of children with autism. Journal of Child Psychology and Psychiatry and allied disciplines, 40(5), pp. 705-718.
Available from the NAS Information Centre

International Molecular Study of Autism Consortium (1998) A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Human Molecular Genetics, 7(3), pp. 571-578.

Kanner, L. (1943) Autistic disturbances of affective contact. Nervous Child, 2, pp. 217-250.
Available from the NAS Information Centre

Lamb, J. A. et al. (2000) Autism: recent molecular genetic advances. Human Molecular Genetics, 9, pp. 861-868.

Lord, C. and Schopler, E. (1987) Neurobiological implications of sex differences in autism. In: Neurobiological issues in autism / edited by E. Schopler and G. Mesibov, New York: Plenum Press, pp. 191-211.
Available from the NAS Information Centre

McKusick, V. et al. 209850 autistic disorder.
www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?209850

Pauls, D. L. (1987)  The familiality of autism and related disorders: a review of the evidence. In: Handbook of autism and pervasive developmental disorders / edited by D. J. Cohen and A. M. Donnellan, New York: Wiley, pp. 192-198.
Available from the NAS Information Centre

Piven, J. and Folstein, S. E. (1994) The genetics of autism. In: The neurobiology of autism / edited by Margaret Bauman and Thomas Kemper,  Johns Hopkins University Press,  pp.18-44.
Available from the NAS Information Centre

Piven, J. and Palmer, P. (1999) Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families. American Journal of Psychiatry, 156(4), pp 557-563.
Available from the NAS Information Centre

Ridley, M. (2000)  Genome: the autobiography of a species in 23 chapters. London: Fourth Estate.

Risch, R. et al (1999) A genomic screen of autism:  evidence for a multilocus etiology. American Journal of Human Genetics, 65(2), pp 493-507.
Available from the NAS Information Centre

Rutter, M. et al. (1993) Autism: syndrome definition and possible genetic mechanisms. In: Nature, nurture and psychology / edited by R. Plomin and G. E. McClearn, Washington DC.: American Psychological Association, pp. 269-284.
Available from the NAS Information Centre

Rutter, M. et al (1994)  Autism and known medical conditions: myth and substance. Journal of Child Psychology and Psychiatry, 35(2), pp. 311-322.
Available from the NAS Information Centre

Skuse, D. H. (2000) Imprinting the X-chromosome, and the male brain: explaining sex differences in the liability to autism. Pediatric Research, 47(1), pp. 9-16.
Available from the NAS Information Centre

Turner, M., Barnby, G. and Bailey, A. (2000) Genetic clues to the biological basis of autism. Molecular Medicine Today, 6, pp. 238-244.
Available from the NAS Information Centre 

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