Disentangling the heterogeneity of autism spectrum disorder through genetic findings

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.

Figure 1

From genes to brain to behaviour—a conceptual framework. The key notion is that genes contribute to behaviour and cognition in ASD via their effects on brain structure and development. Abbreviation: ASD, autism spectrum disorder.

Figure 2

Proposed mechanism underlying the relationship between epilepsy and ASD. The comorbidity of ASD with other neurodevelopmental disorders, such as epilepsy, can be conceptualized in two main ways. In pathway 1, a genetic variant or mutation causes aberrant brain development or function, leading to seizures, which in turn impair early cognitive and social development. In pathway 2, ASD and epilepsy represent two sequelae of a common process, starting from a genetic variant or mutation that leads to aberrant brain development. These scenarios are not mutually exclusive. Abbreviation: ASD, autism spectrum disorder.

Figure 3

Recommendations for clinical genetic testing in children with ASD. Genetic screening in autism should be undertaken in stepwise fashion to integrate clinical history with state-of-the-art testing in the most efficient manner. In all children with ASD, chromosomal microarray analysis should be conducted, as well as detailed family history and clinical examination for signs of known or cryptic genetic syndromes. At this stage, other testing can recommended depending on other phenotypic features, such as the sex of the child or presence of macrocephaly. Genetic counselling is a key component of any clinical genetic analyses. Abbreviations: ASD, autism spectrum disorder; HC, head circumference.