Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders

Abstract

Investigations into the etiology of autism spectrum disorders have been largely confined to two realms: variations in DNA sequence and somatic developmental exposures. Here we suggest a third route—disruption of the germline epigenome induced by exogenous toxicants during a parent’s gamete development. Similar to cases of germline mutation, these molecular perturbations may produce dysregulated transcription of brain-related genes during fetal and early development, resulting in abnormal neurobehavioral phenotypes in offspring. Many types of exposures may have these impacts, and here we discuss examples of anesthetic gases, tobacco components, synthetic steroids, and valproic acid. Alterations in parental germline could help explain some unsolved phenomena of autism, including increased prevalence, missing heritability, skewed sex ratio, and heterogeneity of neurobiology and behavior.

Metabolomic changes in children with autism

“…Genetics plays a significant role in autism, and studies have shown that certain genetic mutations or variations can increase the risk of developing ASD. Some cases of autism are associated with spontaneous mutations that occur in the sperm or egg cells or early in fetal development rather than being inherited from parents[ 20 ]. Certain genetic syndromes, such as Fragile X syndrome or Rett syndrome, have a higher prevalence of ASD.…”

Sensing Echoes: Temporal Misalignment in Auditory Brainstem Responses as the Earliest Marker of Neurodevelopmental Derailment

“…Recent biological evidence supports the notion that at least some forms (and probably the majority) of the broad, heterogeneous developmental disorders within the autism spectrum (ASD) are atypical prior to birth, many linked to genetic origins (11–13). These in turn, may have significant effects on postnatal development (14–17).…”

The impact of paternal age on new mutations and disease in the next generation

“…For example, older fathers are at a high risk of having children with schizophrenia or autism ( 3 , 19 , 20 , 79 , 80 , 81 , 82 ). There is considerable debate as to whether the link between advanced paternal age and these disorders is due to: inherited genetic factors influencing the health of fathers and timing of reproduction (inherited model); testes-driven DNMs that arise randomly as a consequence of aging (de novo model); environmental factors (such as oxidative stress); epigenetic factors that accumulate over time; or (more likely) a combination of the above ( 12 , 50 , 83 , 84 , 85 , 86 , 87 , 88 ). Unraveling the contribution of these factors to the PAE in common disorders is challenging (and beyond the scope of this review), but before this can be attempted, a better understanding of the etiology of these “complex” disorders will be required ( 12 , 89 ).…”