Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands

Abstract

Although the full aetiology of autism spectrum disorder (ASD) is unknown, familial and twin studies demonstrate high heritability of 60-90%, indicating a predominant role of genetics in the development of the disorder. The genetic architecture of ASD consists of a complex array of rare and common variants of all classes of genetic variation usually acting additively to augment individual risk. The relative contribution of heredity in ASD persists despite selective pressures against the classic autistic phenotype; a phenomenon thought to be explained, in part, by the incidence of spontaneous (or de novo) mutations. Notably, environmental exposures attributed as salient risk factors for ASD may play a causal role in the emergence of deleterious de novo variations, with several ASD-associated agents having significant mutagenic potential. To explore this hypothesis, this review article assesses published epidemiological data with evidence derived from assays of mutagenicity, both in vivo and in vitro, to determine the likely role such agents may play in augmenting the genetic liability in ASD. Broadly, these exposures were observed to elicit genomic alterations through one or a combination of: (1) direct interaction with genetic material; (2) impaired DNA repair; or (3) oxidative DNA damage. However, the direct contribution of these factors to the ASD phenotype cannot be determined without further analysis. The development of comprehensive prospective birth cohorts in combination with genome sequencing is essential to forming a causal, mechanistic account of de novo mutations in ASD that links exposure, genotypic alterations, and phenotypic consequences.

Fig. 1. Diagrammatic representation of the interplay between genetic and environmental risk factors in the aetiology of ASD.

Both heritable and non-heritable factors can independently and reciprocally influence the development of ASD symptomatology. Up to 5–15% of ASD probands possess risk-associated de novo mutations, indicating the significance of non-familial genetic variability in determining disorder risk. The mutagenic/genotoxic potential of non-heritable factors associated with ASD suggests that these toxicants may play a role in the elicitation of spontaneous mutations. Figure created with BioRender.com.

Fig. 2. Diagrammatic representation of the impact of environmental factors on genomes within parental germlines and offspring.

ASD-associated toxicants (e.g., herbicides, heavy metals) can induce de novo mutations in parental germline cells which may be transmitted to offspring in the subsequent generation. For example, agent-induced double stranded breaks (DSBs) and impaired BRCA1-directed homologous recombination (HR) DNA damage response (DDR) can elicit de novo mutations and hamper their repair. Offspring may also acquire agent-induced mutations at later stages of development, resulting in somatic mosaicism. Gene(s) impacted by these processes can lead to aberrant neural development and functioning, contributing to the onset of ASD. Figure created with BioRender.com.