Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder

Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction of developmental outcomes. Based on minor physical and major congenital anomalies, we categorized 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We developed a method for calculating a patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD had a significantly higher GRVS compared to those with nondysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in nondysmorphic ASD probands (P= 2.9X10-3). These findings replicated using WGS data from 442 ASD probands with accompanying morphology data from the Simons Simplex Collection. Our results provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

Rates of contributory de novo mutation in high and low-risk autism families

Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52–67% of cases of autism arising from low risk families, and 30–39% of cases of all autism.

Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in a general population are related to ASD risk and common sleep problems like insomnia in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as parent reported sleep disturbances in children diagnosed with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection and MSSNG database, as well as 7463 individuals from two unselected populations (IMAGEN and Generation Scotland). We identified 320 and 626 rare CNVs encompassing circadian genes and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (but not duplications) were also associated with ASD. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Duplications containing circadian genes were associated with shorter sleep duration(22 minutes). Only insomnia risk genes intolerant to haploinsufficiency increased insomnia traits when duplicated. Overall, CNVs encompassing circadian and insomnia risk genes increase ASD risk despite small impacts on sleep disturbances.

Cognitive profiles of children with autism spectrum disorder with parent-reported extraordinary talents and personal strengths

It is essential to recognize the strengths and talents of autistic individuals. Previous studies of extraordinary talents (i.e. skills that stand out relative to the general population) have combined individuals with different skills (e.g. calendrical calculation, drawing) into one group. There has been limited investigation of talents in specific areas and even less consideration of personal strengths (i.e. skills that stand out relative to that person’s other abilities, but not the general population). We extend this literature by examining the relationship between parent-reported talents and strengths and performance on standardized cognitive tests in 1470 children (4–18 years) from the Simons Simplex Collection with autism and IQ above 70. Almost half (46%) had at least one parent-reported talent and an additional 23% without extraordinary talents had at least one personal strength. Children with parent-reported talents and strengths had different cognitive profiles than children with no reported skill in visuospatial, drawing, computation, or music. Those highlighted for their memory abilities had somewhat more even verbal and nonverbal abilities, relative to children whose memory was not emphasized as a special skill. These results emphasize the importance of exploring strengths separately by domain and a need for more research in this area. Lay abstract Previous research has suggested that focusing on impairments can be detrimental to the well-being of autistic individuals, yet little research has focused on strengths and positive qualities in autism. Some studies explored “savant skills” (herein referred to as “extraordinary talents”), that is, skills that stand out compared to the general population. These often group everyone who has a specific talent, rather than exploring subgroups with strengths in specific areas. There has been even less research focused on personal strengths (i.e. skills that stand out relative to the individual’s other abilities, but not the general population). To expand this research, we use a sample of 1470 children (ages 4–18 years) from the Simons Simplex Collection without cognitive impairment to examine the relationship between having a parent-reported skill in a specific area and performance on a standardized cognitive test. Almost half (46%) had at least one parent-reported talent and an additional 23% without extraordinary talents had at least one personal strength. Children with these parent-reported skills had different patterns of performance on these standardized tests than children without skills in that area (i.e. visuospatial, drawing, computation, reading, and memory). Specific skills in computation or reading were associated with higher overall performance on the standardized tests. These results emphasize the importance of considering strengths separately by area, rather than combining individuals with different types of strengths. The high number of children with skills in this study underscores the need for more research in this area, particularly using instruments focused on understanding the nuances of these strengths. It is important for future studies to consider these skills in children with cognitive impairment.

Relationship Between Social Motivation in Children With Autism Spectrum Disorder and Their Parents

Impairment in social motivation (SM) has been suggested as a key mechanism underlying social communication deficits observed in autism spectrum disorder (ASD). However, the factors accounting for variability in SM remain poorly described and understood. The current study aimed to characterize the relationship between parental and proband SM. Data from 2,759 children with ASD (Mage = 9.03 years, SDage = 3.57, 375 females) and their parents from the Simons Simplex Collection (SSC) project was included in this study. Parental and proband SM was assessed using previously identified item sets from the Social Responsiveness Scale (SRS). Children who had parents with low SM scores (less impairments) showed significantly lower impairments in SM compared to children who had either one or both parents with elevated SM scores. No parent-of-origin effect was identified. No significant interactions were found involving proband sex or intellectual disability (ID) status (presence/absence of ID) with paternal or maternal SM. This study establishes that low SM in children with ASD may be driven, in part, by lower SM in one or both parents. Future investigations should utilize larger family pedigrees, including simplex and multiplex families, evaluate other measures of SM, and include other related, yet distinct constructs, such as social inhibition and anhedonia. This will help to gain finer-grained insights into the factors and mechanisms accounting for individual differences in sociability among typically developing children as well as those with, or at risk, for developing ASD.

Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

Individuals with autism spectrum disorders (ASD) exhibit an increased burden of de novo variants in a broadening range of genes. We functionally tested the effects of ASD missense variants using Drosophila through ‘humanization’ rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identified GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

Effects-sizes of deletions and duplications on autism risk across the genome

ABSTRACTObjectiveDeleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, only 13 genomic loci have been formally associated with autism because the majority of CNVs are too rare to perform individual association studies. To investigate the implication of undocumented CNVs in neurodevelopmental disorders, we recently developed a new framework to estimate their effect-size on intelligence quotient (IQ) and sought to extend this approach to autism susceptibility and multiple cognitive domains.MethodsWe identified CNVs in two autism samples (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models integrating scores of genes encompassed in CNVs were used to explain their effect on autism susceptibility and multiple cognitive domains.ResultsAmong 9 scores of genes, the “probability-of-being loss-of-function intolerant” (pLI) best explains the effect of CNVs on IQ and autism risk. Deletions decrease IQ by a mean of 2.6 points per point of pLI. The effect of duplications on IQ is three-fold smaller. The odd ratios for autism increases when deleting or duplicating any point of pLI. This increased autism risk is similar in subgroups of individuals below or above median IQ. Once CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behaviour, and phonological memory, whereas both equally affect motor skills.ConclusionsAutism risk conferred by duplications is less influenced by IQ compared to deletions. CNVs increase autism risk similarly in individuals with high and low IQ. Our model, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk. These models will help interpreting CNVs identified in the clinic.

Large mosaic copy number variations confer autism risk

Although germline de novo copy number variants are a known cause of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. Here, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 ASD probands and 5,500 unaffected siblings in the Simons Simplex Collection (SSC) and Simons Powering Autism Research for Knowledge (SPARK) cohorts. We detected 46 mCNVs in probands and 19 mCNVs in siblings ranging from 49 kb to 249 Mb and affecting 2.8-73.8% of cells. In both cohorts, probands carried a significant burden of large (>4 Mb) mCNVs (P = 0.043 and P = 6.6 × 10−3 in SSC and SPARK, respectively), which were present in a total of 25 probands but only 1 sibling (OR=11.4, 95% CI=1.5-84.2). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD. Event size positively correlated with severity of ASD symptoms (P = 0.016), and four probands exhibited clinical symptoms consistent with syndromes previously associated with genes or regions disrupted by their respective mosaic mutations. In analyses of post-mortem brain tissue from 60 additional probands, we further detected and experimentally validated two mCNVs including a complex 10.3 Mb duplication on chromosome 2. These results indicate that mosaic CNVs contribute a previously unexplained component of ASD risk.

The association of neurofibromatosis and autism symptomatology is confounded by behavioral problems

Aimto evaluate if autism symptoms and diagnoses are raised in children with neurofibromatosis type 1 (NF1), to which levels, and to determine if co-occurring symptomatology accounts for this elevation.MethodWe interrogated our hospital electronic medical records. We collected parental reports of autism symptomatology, adaptive behavior, and co-occurring behavioral and emotional problems on a subsample of 45 children (9 years 2 months, 49% male). Age- and sex-matched controls with (N=180) or without ASD (N=180) were drawn from the Simons Simplex Collection and compared cross-sectionally to participants with NF1.ResultsDiagnoses of ADHD (8.8%), not of ASD (2.1%), were raised among 968 children with NF1 identified through electronic search. Mean Social Responsiveness Score (55.9) was below the cut-off of 60 for significant autism symptoms. Participants with NF1 had significantly more autism and behavioral symptoms than typically developing (TD) controls, and significantly less than controls with autism, with one exception: ADHD symptom levels were similar to those of autistic controls. When emotional, ADHD, and communication scores were covaried, the difference between participants with NF1 and TD controls disappeared almost entirely.InterpretationOur results do not support an association between NF1 and autism, both at the symptom and disorder levels.What this paper addsDiagnoses of ADHD, not of ASD, were raised among children with NF1.Increases in autism symptoms did not reach clinically significant thresholds.Co-occurring ADHD symptoms accounted for increased autism questionnaire scores.Adaptive behavior in NF1 participants showed normal socialization but lower communication proficiency.

Psychometric Properties of the Simons Simplex Collection Sleep Interview

Background and Purpose: An estimated 40%–80% of children with autism spectrum disorders (ASD) have sleep problems. The Simons Simplex Collection Sleep Interview (SSCSI) is a parent-report questionnaire assessing bedtime and nighttime sleep problems and daytime function. The present study evaluated the factorial model of the SSCSI that best characterizes children aged 4–18 years with ASD. Methods: Exploratory factor analysis was performed using principal component analysis and promax rotation, beginning with 16 items and ending with 10 items. Results: Exploratory factor analysis concluded with ten dichotomous items, plus ageand regular sleep duration, in three factors: nighttime problems, daytime problems, andsleep duration problems. The analysis was performed on the full sample, and onprepubertal (4–8-years), pubertal (9–13-years), and postpubertal (14–18-years) subgroups. Conclusion: Further refinement, including confirmatory factor analysis, test–retest reliability, and convergent validity testing, is needed.