Genetic Basis of Autism

Is There a Way Forward?

Valsamma Eapen


Curr Opin Psychiatry. 2011;24(3):226-236. 

In This Article

Abstract and Introduction


Purpose of review This paper outlines some of the key findings from genetic research carried out in the last 12–18 months, which indicate that autism spectrum disorder (ASD) is a complex disorder involving interactions between genetic, epigenetic and environmental factors.
Recent findings The current literature highlights the presence of genetic and phenotypic heterogeneity in ASD with a number of underlying pathogenetic mechanisms. In this regard, there are at least three phenotypic presentations with distinct genetic underpinnings: autism plus phenotype characterized by syndromic ASD caused by rare, single-gene disorders; broad autism phenotype caused by genetic variations in single or multiple genes, each of these variations being common and distributed continually in the general population, but resulting in varying clinical phenotypes when it reaches a certain threshold through complex gene–gene and gene–environment interactions; and severe and specific phenotype caused by 'de-novo' mutations in the patient or transmitted through asymptomatic carriers of such mutation.
Summary Understanding the neurobiological processes by which genotypes become phenotypes, along with the advances in developmental neuroscience and neuronal networks at the cellular and molecular level, is paving the way for translational research involving targeted interventions of affected molecular pathways and early intervention programs that promote normal brain responses to stimuli and alter the developmental trajectory.


Autism spectrum disorder (ASD) is one of the most familial of psychiatric disorders, with a heritability of 80%.[1] Twin and family studies have demonstrated a monozygotic concordance rate of 70–90%, dizygotic concordance of around 10% and more than a 20-fold increase in risk for first-degree relatives.[2,3] Despite some notable findings in the recent past,[4••,5] the rate of progress in gene discovery has been modest.[6] So far, around 103 genes and 44 genomic loci have been reported in ASD[7] with considerable overlap with other disorders such as intellectual deficiency, epilepsy, schizophrenia and attention deficit hyperactivity disorder (ADHD), suggesting that ASD is not a single-gene disorder with Mendelian inheritance but rather a complex disorder resulting from simultaneous genetic variations in multiple genes[8] as well as complex interactions between genetic, epigenetic and environmental factors.

Further, it is suggested that some of the associated sequence variations noted in ASD are common in the general population. However, it is not clear whether the involvement of single genes in combination with nongenetic factors or multiple genes through locus heterogeneity (multiple rare variations in the same gene) or multiple genes through allelic heterogeneity (variations in multiple and different genes) is needed to result in the ASD phenotype. It is also suggested that multiple genes in combination with nongenetic factors may be in operation and that is needed to result in the ASD phenotype. It has also been suggested that ASD may well be a collection of rare disorders resulting from several different genetic defects leading to a shared phenotype. Questions also remain as to 'how many' genes are involved and 'how big' the changes in the allelic structure are. Recently, a two-component model was suggested,[9] in which ASD is considered to be caused either by 'de-novo' mutation or by dominant inheritance from asymptomatic carriers of such a mutation.


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