We searched PubMed for papers published in English between Jan 1, 1995, and Feb 28, 2015, using the terms “autism” and “genetics”. Articles were also identified through searches of the reference lists of selected papers and the authors' personal files. The final selection was based on relevance to the topics covered in this Series paper.
SeriesGene hunting in autism spectrum disorder: on the path to precision medicine
Introduction
The term autism spectrum disorder (ASD) defines a neurodevelopmental syndrome that affects about one in 100 people worldwide, and is characterised by early dysfunction in social interactions and the presence of repetitive and restrictive behaviours.1 ASD is consistently reported to be more prevalent in boys than in girls.1 People with ASD have a broad range of phenotypes and commonly also have intellectual disability (35%), language delay (50%), or epilepsy (5–15%). Until a decade ago, little was known about the causes and pathogenic mechanisms of ASD. Although, in general, strong evidence indicates that the causes include both genetic and environmental factors,2 genetic research over the past decade has taken the leading role in the elucidation of pathophysiology. Strikingly, ASD is one of a relatively small number of neuropsychiatric conditions for which substantial progress in gene discovery has been made during this period. This progress has been a result of conceptual and technological advances in the study of genetics of human disease, highly effective advocacy and philanthropy that has led to large study cohorts and widespread data sharing, and an evolving and maturing view of the role of common and rare genetic variation in human disease.3 Advances in the genetics of ASD have therefore provided both insight into the neurobiology of a complex disorder and a template for understanding the genetics and genomics of other common neuropsychiatric conditions.
In this Series paper, we describe basic concepts in the genetic architecture of common human disease, contrasting the concept of rare, penetrant mutations with common genetic variation. We review progress in the identification of ASD genes, including studies of genetic linkage, analysis of copy number variants (CNVs), whole-genome association, and exome sequencing to identify rare transmitted and de novo variation. We also discuss the endophenotype concept and its use in gene discovery. Finally, we consider the promise of these genetic findings for understanding the pathophysiology of ASD, and highlight some of their important clinical implications.
Section snippets
Genetic variation and human disease
Sequencing of the human and other mammalian genomes over the past decade has provided a foundational set of tools to begin to understand human genetic variation (panel 1). Because most living humans are the progeny of rapid expansion of the human population from a relatively small number of remote ancestors (about 10 000 years ago), we share large segments of our genomes and hence a substantial amount of genetic variation with other humans.4 This so-called common variation is formally defined
Linkage studies
In view of the strong evidence for the heritability of ASD, early genetic studies focused largely on ascertaining multiply affected (multiplex) pedigrees to support genetic linkage analysis aimed at identifying chromosomal regions co-inherited by those with the disorder.14 This approach to the search for heritable variation within families is supported by the more than ten-times increased risk to a sibling of a proband with autism versus the population risk, and the observation of sub-threshold
Towards a new neurology of ASD
The genetic advances outlined above make it clear that ASD is a common syndrome that comprises, at least in part, several hundred rare disorders. Similar heterogeneity must be expected for the role of common variants and rare, intermediate effect-size alleles that have yet to be found. Thus, from any perspective, understanding of ASD is complicated by extreme genetic complexity and heterogeneity. Moreover, substantial challenges to translating even the most robust genomic findings into an
Clinical relevance
At present, rare ASD-related mutations are anticipated in 20–40% of clinical samples.58 An important related issue is whether and how genetic diagnoses will play a key part in clinical assessment and care. Clearly, at present, the identification of rare forms of autism can provide relevant clinical information. For example, the identification of FMR1 mutations in a proband will have obvious implications for family counselling, including increased vigilance for learning disability in related
Conclusions
The combination of advances in ASD genetics, the rapidly declining costs of next-generation sequencing, and the widespread deployment of electronic medical records will enable novel and potentially powerful approaches to the use of accumulating clinical data to advance research. The potential for large-scale investigations of this type has been well demonstrated in data-mining studies based solely on clinical data in ASD,94 and one can easily imagine that the combination of routine clinical
Search strategy and selection criteria
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