Autism is a he terogeneous syndrome that is defined by impairments in three core domains — social interaction, language and restricted and/or repetitive behaviour.
Defined mutations, genetic syndromes and de novo copy number variation probably account for about 10–20% of autism spectrum disorder (ASD) cases, with none of these known causes accounting for more than 1–2%.
None of the molecules or syndromes currently linked to the ASDs has been proven to selectively cause autism. Instead, each seems to result in an array of abnormal neurobehavioural phenotypes, including ASDs and non-syndromic mental retardation.
Understanding why these mutations lead to ASDs in only a subset of cases — through identification of genetic and/or environmental modifiers — will help to clarify how the specific aspects of cognition and behaviour are ultimately shaped.
The identification of molecular links between distinct ASD-related syndromes will lead towards the identification of key signalling pathways that are dysregulated in the ASDs.
Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
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We gratefully acknowledge the families who have made these studies possible — along with the vision and leadership of AGRE and Autism Speaks. We are similarly indebted to the investigators whose work drives this field forward, many of whom we were unable to cite owing to space limitations. Thanks also to E. Herman, R. Mar-Heyming, B. Fogel and other members of the Geschwind laboratory for discussions. We also thank the anonymous reviewers. Work in the Geschwind laboratory is supported by funding from Autism Speaks, the Cure Autism Now Foundation, the National Institue of Mental Health (STAART - U54 MH68172; ACE - P50 HD055784; AGRE R01 MH64547; Asymmetry R37 MH60233) and the Tourette Syndrome Association.
- Gene association studies
A set of methods that is used to determine the correlation (positive or negative) between a defined genetic variant and a phenotype of interest.
- Whole-genome linkage study
A statistical evaluation of genetic variation throughout the genome that is used to identify polymorphic loci that segregate with a phenotype of interest.
- Copy number variation
(CNV). The insertion or deletion of a relatively large DNA fragment (>50 kb).
- Relative risk
The ratio of disease incidence in two groups of individuals that differ with regards to any associated factor (such as genetic polymorphism, environmental exposure or perinatal insult).
- Community-based cohort
A group of individuals that have been selected randomly from a population (as opposed to those showing a specific phenotype of interest).
The proportion of phenotypic variation that is attributable to inherited genetic factors (in contrast to environmental ones).
A measurable trait that is both heritable and related to a specific aspect of a condition under investigation.
- Hierarchical clustering
A statistical method in which a collection of objects (observations, individuals or risk loci) are grouped into subsets, such that those within each cluster are more closely related to one another than objects that are assigned to different clusters.
- Principal components analysis
A statistical method used to simplify data sets by transforming a series of correlated variables into a smaller number of uncorrelated factors.
The frequency with which individuals that carry an allele of a given gene will show the manifestations associated with the variant. If the penetrance of a disease allele is 100% then all individuals carrying that allele will express the associated disorder.
Showing a structural abnormality of a body part or facial feature.
A chromosomal segment that is located between the centromere and telomere.
A genetic abnormality characterized by the presence of two additional and identical DNA segment copies that are joined end to end to form a forty-seventh chromosome.
- Syndromic ASD
An ASD case that is observed in the context of a recognized syndrome (for example, fragile X syndrome).
- Mirror neuron
A neuron that is active when a subject is observing or imagining a motor movement; mirror neurons are thought to underlie imitation.
- Joint attention
Sharing interest or experience with another person by pointing or following gaze.
- Pragmatic language
Practical, social use of language.
A member of a family of postsynaptic cell-adhesion molecules that is important in regulating the balance of inhibitory and excitatory neurotransmission.
Multiplex families are those in which multiple individuals have a clinically diagnosed ASD.
Simplex families are those in which only a single individual has a clinically diagnosed ASD.
- Autistic regression
Normal development until the age of two with a subsequent loss of skills within core ASD domains.
Head circumference greater than two standard deviations above the mean (the ninety fifth percentile).
- Multiple comparisons
Refers to the problem that arises when many null hypotheses are tested and 'significant' differences are observed when in reality there are no differences.
- Frontal executive
Frontal executive function describes broad aspects of higher cognition (for example, attention, working memory and relational reasoning) that are mediated by the frontal lobe and interconnected subcortical circuitry.
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Abrahams, B., Geschwind, D. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9, 341–355 (2008). https://doi.org/10.1038/nrg2346
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