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Disentangling the heterogeneity of autism spectrum disorder through genetic findings

Nature Reviews Neurology volume 10, pages 74–81 (2014)Cite this article

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Key Points

  • Over the past 5 years, researchers have identified many genetic factors that increase the risk of autism spectrum disorder (ASD), and that might shed light on more-homogeneous subgroups within the spectrum

  • The most robustly identified genetic risks for ASD are rare mutations with large effect; studies have been underpowered to detect common genetic variation

  • The role of rare genetic variants supports the relevance of studying monogenic disorders, such as tuberous sclerosis complex, for understanding ASD pathophysiology

  • The most parsimonious explanation for the male predominance in ASD involves the presence of protective factors that reduce the risk of ASD in females

  • Many genetic mutations associated with ASD also confer high risk of comorbidities including epilepsy, motor impairment and sleep disturbance

  • Genetic testing including chromosomal microarray analysis is warranted and clinically indicated for all suspected cases of ASD

Abstract

Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment.

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Figure 1: From genes to brain to behaviour—a conceptual framework.
Figure 2: Proposed mechanism underlying the relationship between epilepsy and ASD.
Figure 3: Recommendations for clinical genetic testing in children with ASD.

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Authors and Affiliations

  1. Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Suite 68-237, Los Angeles, 90064, CA, USA

    Shafali S. Jeste

  2. University of California Los Angeles, Gonda Research Building, Room 2506, 695 Charles E. Young Drive South, Los Angeles, 90095, CA, USA

    Daniel H. Geschwind

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S. S. Jeste researched data for the article. Both authors made substantial contributions to discussion of the content, writing of the article, and to review and/or editing of the manuscript before submission.

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Correspondence to Shafali S. Jeste.

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Jeste, S., Geschwind, D. Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat Rev Neurol 10, 74–81 (2014). https://doi.org/10.1038/nrneurol.2013.278

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