Genomic Patterns of De Novo Mutation in Simplex Autism

To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10-8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10-3, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10-3), suggesting a path forward for genetically characterizing more complex cases of autism.

Keywords: attributable fraction; autism; de novo mutation; genome sequencing; mechanisms of disease; multifactorial genetics; noncoding; oligogenic; regulatory.

Objective: Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci.

Method: Analyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains.

Results: Children with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences).

Conclusions: Children with ASD with de novo mutations may exhibit a “muted” symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first.

Keywords: Autism Spectrum Disorder; De Novo Mutations; Idiopathic ASD; Phenotype; Simons Simplex Collection; Syndromic ASD.

Whole-exome and whole-genome sequencing have facilitated the large-scale discovery of de novo variants in human disease. To date, most de novo discovery through next-generation sequencing focused on congenital heart disease and neurodevelopmental disorders (NDDs). Currently, de novo variants are one of the most significant risk factors for NDDs with a substantial overlap of genes involved in more than one NDD. To facilitate better usage of published data, provide standardization of annotation, and improve accessibility, we created denovo-db (http://denovo-db.gs.washington.edu), a database for human de novo variants. As of July 2016, denovo-db contained 40 different studies and 32,991 de novo variants from 23,098 trios. Database features include basic variant information (chromosome location, change, type); detailed annotation at the transcript and protein levels; severity scores; frequency; validation status; and, most importantly, the phenotype of the individual with the variant. We included a feature on our browsable website to download any query result, including a downloadable file of the full database with additional variant details. denovo-db provides necessary information for researchers to compare their data to other individuals with the same phenotype and also to controls allowing for a better understanding of the biology of de novo variants and their contribution to disease.

Sensory symptoms, including auditory processing deficits, are common in autism spectrum disorder (ASD). Processing of temporal aspects of auditory input is understudied; yet, deficits in this domain could contribute to language-related impairments. In children with ASD and well-matched controls, this study examined electrophysiological response to silent gaps in auditory stimuli. Results revealed attenuated amplitude of the P2 event-related potential (ERP) component in ASD. The P2 amplitude reduction was also associated with sensory, language, and diagnostic features. These results suggest that neural response during auditory gap detection is a promising ASD biomarker that could be useful for stratifying subgroups and evaluating treatment response.

Electroencephalography (EEG) offers information about brain function relevant to a variety of neurologic and neuropsychiatric disorders. EEG contains complex, high-temporal-resolution information, and computational assessment maximizes our potential to glean insight from this information. Here we present the Batch EEG Automated Processing Platform (BEAPP), an automated, flexible EEG processing platform incorporating freely available software tools for batch processing of multiple EEG files across multiple processing steps. BEAPP does not prescribe a specified EEG processing pipeline; instead, it allows users to choose from a menu of options for EEG processing, including steps to manage EEG files collected across multiple acquisition setups (e.g., for multisite studies), minimize artifact, segment continuous and/or event-related EEG, and perform basic analyses. Overall, BEAPP aims to streamline batch EEG processing, improve accessibility to computational EEG assessment, and increase reproducibility of results.

Keywords: EEG; MATLAB; automated; batch; electroencephalography; reproducibility; signal processing.

Background: Social communication impairments associated with Autism Spectrum Disorder (ASD) is a multi-faceted phenomenon that encapsulates a broad range of skills with Theory of Mind (ToM) as a key component. Early Theory of Mind (ToM) skills, such as joint attention, typically develop during infancy and provide a foundation for the co-emergence of affect regulation via social referencing. Children with Autism Spectrum Disorder (ASD) demonstrate delays and impairments in the development of ToM, and up to 40% of children with ASD also experience co-occurring symptoms of anxiety and poor affect regulation. Method: Using parent report, this cross-sectional study aimed to characterise the relationship between ToM competency and anxiety, and explore how specific ToM deficits may confer vulnerability to anxiety in children (4–8 years old) with ASD. Results: Early ToM skills, such as joint attention and social referencing, mediated the relationship between broader social communication impairments and anxiety symptom severity in children with ASD. Conclusions: Increasing competency of early ToM skills might provide additional therapeutic benefits for clinical interventions targeting anxiety in children with ASD.

Autism Spectrum Disorders (ASD)
Theory of Mind (ToM)
Joint attention
Anxiety

Recent studies suggest that circumscribed interests (CI) in females with Autism Spectrum Disorder (ASD) may align more closely with interests reported in typical female development than those typically reported for ASD males. We used eye-tracking to quantify attention to arrays containing combinations of male, female and neutral images in elementary-aged males and females with and without ASD. A number of condition × sex effects emerged, with both groups attending to images that corresponded with interests typically associated with their biological sex. Diagnostic effects reported in similar studies were not replicated in our modified design. Our findings of more typical attention patterns to gender-typical images in ASD females is consistent with evidence of sex differences in CI and inconsistent with the “Extreme Male Brain” theory of ASD.

Keywords: Circumscribed interests; Extreme Male Brain theory; Eye-tracking; Females; Sex differences.