The Genetic Landscapes of Autism Spectrum Disorders

Huguet, Guillaume; Ey, Elodie; Bourgeron, Thomas

doi:10.1146/annurev-genom-091212-153431

Cited by 392 publications

(324 citation statements)

References 132 publications

Supporting

Mentioning

318

Contrasting

Unclassified

Order By: Relevance

“…ASD has a significant genetic component, with up to 25% of cases being caused by an identifiable genetic defect (Huguet et al 2013). However, two recent epidemiologic studies have concluded that environmental influences have a greater contribution than genetic factors in the etiology of autism (Hallmayer et al 2011;Sandin et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism

Widjaja

et al. 2016

Journal of Child and Adolescent Psychopharmacology

102

View full text Add to dashboard Cite

Objective: Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. Methods: A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 lg/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks.Results: A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure -the clinician rated CGI-I score -was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2-0.2, p = 0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine ( p = 0.05), decreases in S-adenosyl-lhomocysteine (SAH) ( p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH ( p = 0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. Conclusions: Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry: Efficacy Study of Subcutaneous Methyl B12 in Children with Autism: NCT01039792 (clinical trials.gov1).

show abstract

Section: Introductionmentioning

confidence: 99%

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism

Widjaja

et al. 2016

Journal of Child and Adolescent Psychopharmacology

102

View full text Add to dashboard Cite

show abstract

“…essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1,2). The highly polygenic nature of ASD (3)(4)(5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function.…”

mentioning

confidence: 99%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre-and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1, 2). The highly polygenic nature of ASD (3-5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6). However, combined analyses of de novo, inherited, and case-control variation in over 2,500 ASD parentchild nuclear families identified around 100 genes contributing to ASD risk (7-9), converging on pathways implicated in transcriptional regulation and chromatin modeling in addition to synaptic function.The main challenge in the current understanding of genetic architecture of ASD comes from a need to study the interplay between variants with a high effect (for example, recurrent de novo variants) and a background of variants with an intermediate effect but that nevertheless still disrupt proper neuronal development. Essential genes (EGs) or genes that are necessary for successful completion of pre-and postnatal development are prime candi...

show abstract

“…Studies of common SNPs, rare SNVs and CNVs, in the context of ID and ASD, have together yielded thousands of genes in which variation may contribute differing degrees of risk for the development of these disorders, and/or influence the severity of the disorder (Huguet et al 2013;van Bokhoven 2011). Among this collection of genes we can attempt to identify biological themes that are useful to narrow the search space for language-related genes, for example in prioritizing variants identified from next-generation sequencing data (Deriziotis and Fisher 2013).…”

Section: Intellectual Disability and Autism Spectrum Disordersmentioning

confidence: 99%

“…Among this collection of genes we can attempt to identify biological themes that are useful to narrow the search space for language-related genes, for example in prioritizing variants identified from next-generation sequencing data (Deriziotis and Fisher 2013). Unsurprisingly, synaptic homeostasis is an overarching theme in ID/ASD genetics, including categories of proteins such as ion channels, cell adhesion molecules, signal transduction proteins, and proteins involved in mRNA metabolism and chromatin modification (Huguet et al 2013;Srivastava and Schwartz 2014;Pinto et al 2014). …”

Section: Intellectual Disability and Autism Spectrum Disordersmentioning

confidence: 99%

Insights into the Genetic Foundations of Human Communication

2015

View full text Add to dashboard Cite

The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.

show abstract

The Genetic Landscapes of Autism Spectrum Disorders

Cited by 392 publications

References 132 publications

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Insights into the Genetic Foundations of Human Communication

Contact Info

Product

Resources

About