Progress in the genetics of autism spectrum disorder

Woodbury‐Smith, Marc; Scherer, Stephen W.

doi:10.1111/dmcn.13717

Cited by 150 publications

(86 citation statements)

References 66 publications

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“…We decided to classify these variants as potentially causative even if the proband's phenotypes were only partially consistent with the phenotype reported for each gene. In these cases, to support the pathogenic role of the variants we considered the complex genetic architecture underlying the pathogenic mechanisms involved in NDDs (Woodbury‐Smith & Scherer, ). The p.Arg696His in GRIN2B gene has been previously reported in an individual with ID but no macrocephaly, and experimentally tested for its ability to impair the protein function (Swanger et al, ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

et al. 2019

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Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low‐cost next‐generation sequencing gene panel that has been transferred into clinical practice, replacing single disease‐gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease‐gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease‐causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

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Section: Discussionmentioning

confidence: 99%

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

et al. 2019

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“…These include, but are not limited to, realistic cost-benefit analyses, genetic data protection, clinical guideline development, and the avoidance of discrimination of genetic and ethnic minorities. 46,47,6 Conclusions This is the first study to show that individuals with ASD and large rare genic CNVs are less likely than non-carriers to benefit from SSGT. Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.…”

Section: Discussionmentioning

confidence: 76%

“…Genetic factors, both common and rare play a significant part in the etiology of the disorder with complex interplay with each other and environmental factors. 6,7 There is a scarcity of evidence-based interventions for ASD. 8 A commonly used intervention to ameliorate social communication difficulties and their negative impact on adaptive outcomes in the normative intellectual range of ASD is social skills group training (SSGT).…”

Section: Introductionmentioning

confidence: 99%

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Tammimies

Rabkina

et al. 2018

Preprint

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Challenges in social communication and interaction are core symptoms in autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention.SSGT has shown modest but heterogeneous effects in clinical trials, and therefore identification of effect moderators could enable more precise intervention decisions. One of the major genetic risk factors in ASD are rare copy number variation (CNV). However, limited information exists whether rare CNVs profiles can be used to aid in intervention decisions. Therefore, we conducted the first study to date analyzing rare CNVs as genetic moderators in the outcome of SSGT in ASD. For this, we analyzed rare genic CNV carrier status of 207 children of which 105 received SSGT and 102 standard care as part of a recent randomized clinical trial for 12-weeks SSGT. We used mixed linear models to assess the association of being a CNV carrier, grouped by the effect and size of the CNVs and the primary response to SSGT, the parent-report Social Responsiveness Scale (SRS) measured at post-intervention and 3-months follow-up. Additionally, we analyzed the secondary outcome assessments included parent-rated adaptive behaviors (ABAS-II) and trainer-rated clinical global impression (CGI). We show that being a carrier of any size rare genic CNV did not impact on the SSGT outcome. However, when stratifying the groups by size of the CNVs, we identified that carriers of large CNVs (>500 kb) showed inferior SRS outcomes at post-intervention (β = 15.35, 95% CI 2.86-27.84, P=0.017) and follow-up (β = 14.19, 95% CI 1.68-26.70, P=0.028). Similar results were shown for the parent-rated secondary outcome. In contrast, the carriers of small CNVs had better outcome at post-intervention (β = -1.20, 95 % CI -2.0 --0.4 P = 0.003) but not at follow-up for the trainer-rated secondary outcome CGI. These results remained when we tested the specificity of the effect by including the standard care group and adjusting for IQ levels. While our study suggests that being a carrier of any size rare genic 3 CNV did not impact the outcome, it provides preliminary evidence that carriers of high-riskCNVs might not benefit on SSGT as much as non-carriers. Our results indicate that genetic information eventually might help guide personalized intervention planning in ASD. We additionally highlight that more research is needed to understand the intervention needs of autistic individuals with specified molecular alterations.

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“…Autism is a complex neurodevelopmental condition characterized by difficulties in social communication and the presence of repetitive, restrictive behaviors [American Psychiatric Association, 2013]. Studies demonstrate that the underlying genetic etiology is extremely heterogeneous with hundreds of loci implicated to date, and up to 1,000 genes predicted to contribute to autism risk [Chaste, Roeder, & Devlin, 2017;Geschwind & State, 2015;Woodbury-Smith & Scherer, 2018]. With the introduction of massively parallel sequencing, the list of candidate genes connected to autism risk is on the rise [Iossifov et al, 2012;Iossifov et al, 2014;Neale et al, 2012;O'Roak et al, 2012;Sanders et al, 2012;Satterstrom et al, 2018].…”

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confidence: 99%

Three Brothers With Autism Carry a Stop‐Gain Mutation in the HPA‐Axis Gene NR3C2

et al. 2020

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Whole exome sequencing and copy‐number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop‐gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This variant was maternally inherited and provides further evidence for a connection between the NR3C2 and autism. Interestingly, the NR3C2 gene encodes the MR protein, a steroid hormone‐regulated transcription factor that acts in the hypothalamic–pituitary–adrenal axis and has been connected to stress and anxiety, both of which are features often seen in individuals with autism. Autism Res 2020, 13: 523–531. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Given the complexity of the genetics underlying autism, each gene contributes to risk in a relatively small number of individuals, typically less than 1% of all autism cases. Whole exome sequencing of three brothers with autism identified a rare variant in the nuclear receptor subfamily 3 group C member 2 gene that is predicted to strongly interfere with its normal function. This gene encodes the mineralocorticoid receptor protein, which plays a role in how the body responds to stress and anxiety, features that are often elevated in people diagnosed with autism. This study adds further support to the relevance of this gene as a risk factor for autism.

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Progress in the genetics of autism spectrum disorder

Cited by 150 publications

References 66 publications

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Three Brothers With Autism Carry a Stop‐Gain Mutation in the HPA‐Axis Gene NR3C2

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