Until recently, autism spectrum disorders (ASD) were viewed as a relatively rare condition. Increased awareness and recognition has led to increased diagnostic rates and now the prevalence of ASD is thought to be relatively common, affecting about 1/150 people in the population.
Genetic risk factors are well recognised as playing a predominant role in ASD. Early evidence for this was identified in twin studies in the 1970s.
These studies compare the rate of a condition such as ASD in identical twins (who share 100 per cent of their DNA) with non-identical twins (who typically share 50 per cent of their DNA).
A large number of such studies have consistently found that if one of a pair of identical twins is autistic, the chance that the other one will be too is 60-90 per cent, while the concordance rate in non-identical twins is less than 30 per cent.
Family studies have shown that the risk of having ASD is 10-20 per cent if you have an affected first-degree relative.
Modern genetic tools, especially DNA sequencing technologies, now provide the means to investigate the role of genetic factors in a large number of individuals at a much higher resolution than previously.
The costs of these studies have fallen considerably and this has led to several large-scale international studies of autism genetics that have included Irish families.
A major finding to emerge is that many cases of autism are caused by rare genetic mutations, which can be recognised currently in 15-20 per cent of cases and this is likely to increase as more studies are completed.
Inherited mutations
Some of the time, these mutations are inherited from the parents, but in many cases they are associated with new mutations – ones that arose
de novo
(afresh) in the generation of sperm or egg cells.
These de novo mutations, which are not carried by the parents, can give rise to sporadic cases of autism, with a genetic cause but no family history. It is now possible to screen for many of these mutations and to advise people about recurrence risks.
This is hugely important to couples with a child with ASD who frequently overestimate their risk of having another child with ASD.
Often couples choose not to have more children but if a child has been affected by a de novo mutation, the risk of another child being affected is no higher than the general population.
It is also clear that some families carry very high genetic risks for ASD, due to inherited mutations.
Screening for rare mutations in families with autism has become a standard of care in many countries and is increasingly being conducted in Ireland.
This has led to the identification of a growing number of specific genetic conditions, which can sometimes cause ASD.
Such mutations do not always specifically lead to autism, however. They can also occur in patients with other symptoms, such as epilepsy, schizophrenia or other neurological or psychiatric conditions, and sometimes occur in a very small number of typically developing people.
Autism is thus one of a range of possible clinical manifestations of mutations that alter brain development or function.
Researchers at Trinity College Dublin, NUI Galway and Autism Speaks are currently holding a consultation regarding the establishment of an autism registry and biobank (iarb.ie). A clinical registry will help establish the scale of autism in Ireland and the needs of the community while a biobank of biological materials, such as blood and saliva, would provide researchers with data to investigate the genetic factors that may contribute to autism.
Biological processes
Research suggests that up to 400 genes may be affected by mutations to increase ASD risk. Many of these mutations impact on biological processes involved in development of the brain and how it is wired, often affecting the connections between nerve cells.
It has been possible to identify convergent effects of many of these mutations on a small number of specific molecular pathways within cells, providing optimism about the development of new treatments to reduce ASD symptoms and improve quality of life.
Some of these pathways have previously been identified in related neurodevelopmental conditions such as Fragile X syndrome or Rett syndrome.
Most exciting is that new therapies have been developed based on increased biological understanding for these syndromes and are now being trialled in ASD.
The finding that ASD can result from mutations in so many different genes reinforces the long-held view that ASD is not a unitary condition, but rather an umbrella term that is used to refer to patients with similar sets of symptoms.
Single genetic cause
For some individuals this syndrome may be due to an identifiable single genetic cause.
For others, the risks are likely to be a combination of multiple genetic and non-genetic factors. Statistical risk of ASD is increased slightly with obstetric complications, pre-term birth, being small for gestational age or delivery by Caesarean section, though it is difficult to distinguish cause from effect in these cases.
Non-genetic factors also influence brain development intrinsically, even between genetically identical individuals, ie by the time identical twins are born, their brains are already highly unique.
Importantly, there is currently little evidence for an important role for environmental factors in causing autism.
Proven treatments for ASD are largely behavioural interventions such as Applied Behaviour Analysis (ABA) and other parenting interventions, eg the Denver Early Start Model which combines ABA with relationship-focused interventions encouraging highly responsive interactions between parents and children.
Interventions to support developmental delays in speech and language and sensory motor functioning are also beneficial. Early interventions have been shown to limit the extent of the condition and to prevent additional behavioural problems.
Some people with ASD may need treatment for associated conditions such as epilepsy or other mental health problems.
The recent advances in genetics and neuroscience are giving us a much clearer picture of the causes of ASD and providing genetic diagnosis for a small number of cases.
Future work aims to translate these discoveries into the development of new therapies and more personalised care based on a deep understanding of the causes in individual patients.
Prof Louise Gallagher is chair and Professor of Child and Adolescent Psychiatry in TCD, and leads a research group investigating genetics, brain function and conditions associated with ASD.
Dr Kevin Mitchell is Associate Professor of Genetics and Neuroscience at Trinity College Dublin .
