Autism Spectrum Disorders: Genes and Genomic Mechanisms


Autism spectrum disorder is a gene‐associated disease with strong indications for environmental interaction resulting in appreciable de novo mutations that link to genes that carry functions nested within neural and immune loci. Major functions of these genes are as transcription factors, adhesion molecules, metabolic regulatory enzymes and signalling proteins. Associated with the syndromic mutations are a cluster of genes that support their functionality via a network of activity that is developmentally linked to neural development and the immune response. The mechanism that connects these diverse genomic associations may involve deoxyribonucleic acid (DNA) damage repair and chromosomal instability that have complementing recombination, excision, duplication and substitution reactions along with epigenetic modifications. This suggested mechanism would alter both the level and timing of gene expression at specific loci. The immune response may play a key role in the occurrence and severity of autism. Future research should include careful analyses of these potential genomic mechanisms that may not in themselves present with specific nucleotide variations, but rather with an alteration of chromatin remodelling as modified by inflammation and repair at discrete periods of early neural development.

Key Concepts

  • Autism spectrum disorder genes are diverse in structure and function but have a common link to neural development and the immune response.
  • Genetic alterations including single nucleotide variations/polymorphisms are one element of autism genomics.
  • Copy number variations and alteration in gene product level and timing of expression are part of the mechanism for the variation in syndromic autism genomics.
  • Proinflammatory cytokines play a significant role in autism spectrum disorders and these may be expressed and secreted in response to environmental stimuli including infection with pathogens during gestation and antigen presentation during pregnancy and early childhood development.
  • A potential mechanism linking the immune response to discrete autism associated genetic mutations may involve chromatin instability and remodelling and DNA repair.

Keywords: autism spectrum disorder; proinflammatory cytokines; neural developmental genomics; chromatin instability; autism‐linked gene expression; genetics of neuroimmune activation

Figure 1. Hypothetical model for genomic mechanisms leading to ASD. In utero or postpartum production of molecular pathways that may resolve before or immediately after receptor stimulation (via danger activated molecular patterns – DAMPS and toll like receptor – TLRn mediation) yields no disease (failure to respond or elicit signalling). If signalling proceeds, innate immune cell populations (e.g. macrophages, dendritic cells) transform into antigen presenting cells (APC) that either resolve via innate mechanisms (phagocytosis, detoxification, apoptosis) or proceed to lymphocyte activation (B and T cells) that either promote proinflammatory cytokine and chemokine secretion or undergo DDR directly. Inflammation can resolve due to anergy, T reg cell co‐stimulation or cell death or proceed to target (e.g. neuronal) cell DDR which may generate loci‐specific mutations, copy number variations (CNV) or RNA processing (Splice Variation) errors that ultimately lead to autism spectrum disorder (ASD) syndromic gene alteration and disease presentation. Model infers some form of syndromic pre‐ or co‐disposition to chromosomal instability at actively expressed neuronal loci. Epigenetic mechanisms may take similar routes that involve DNA methylation or histone modification during chromatin remodelling. See text for more detail.


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Further Reading

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Guerra, Daniel J(Mar 2017) Autism Spectrum Disorders: Genes and Genomic Mechanisms. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025846]