SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)

Abrahams, Brett S.; Arking, Dan E.; Campbell, Jerry L.; Mefford, Heather C; Morrow, Eric M.; Weiss, Lauren A.; Menashe, Idan; Wadkins, Tim; Banerjee-Basu, Sharmila; Packer, Alan

doi:10.1186/2040-2392-4-36

Cited by 681 publications

(819 citation statements)

References 8 publications

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“…To initially explore the overlap between EGs and known ASD genes, we examined the essentiality status of ∼500 ASD candidate genes from the Simons Foundation Autism Research Initiative (SFARI) AutDB database (updated December of 2015) (37) (Fig. 2B).…”

Section: Resultsmentioning

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.

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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...

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Section: Resultsmentioning

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.

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“…Human genetic studies and brain imaging data have established MET as a risk factor for autism sprectrum disorder (ASD), a highly heritable psychiatric disorder with disrupted ontogeny of neural connectivity (Campbell et al, 2006(Campbell et al, , 2007Jackson et al, 2009;Sousa et al, 2009;Thanseem et al, 2010;Abrahams et al, 2013). We have previously shown that the rs1858830 'C' allele reduces MET mRNA and protein levels in the brains of subjects with autism through altered interactions with identified transcription factors, providing a potential molecular basis for increased ASD risk (Campbell et al, 2006(Campbell et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

MET Receptor Tyrosine Kinase Controls Dendritic Complexity, Spine Morphogenesis, and Glutamatergic Synapse Maturation in the Hippocampus

2014

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The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk.

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“…A more recent example that is specifically focused on autism genomic results is SFARI Gene 2.0 organized by the Simons Foundation [15]. Platforms such as these are designed to share and present data from genetic testing patients among researchers [5,14,15]. Professionals involved with this project can analyze a bank of test results recorded from patients to identify previously unidentified mutated genes which may contribute to the cause of ASD and other genetic disorders [5,6].…”

Section: Doi: 107243/2054-992x-4-4mentioning

confidence: 99%

“…One such example is DECIPHER Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources) with the appropriate characters italicized hosted by the International Standard Cytogenic Array Consortium, which serves as an as online password-protected storage system of genetic tests results [5,14]. A more recent example that is specifically focused on autism genomic results is SFARI Gene 2.0 organized by the Simons Foundation [15]. Platforms such as these are designed to share and present data from genetic testing patients among researchers [5,14,15].…”

Section: Doi: 107243/2054-992x-4-4mentioning

confidence: 99%

Can genetic research motivate parents to pursue genomic testing for children with autism spectrum disorder?

Floyd¹,

Liu²

2017

J Autism

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Advanced genomic tests such as Chromosomal Microarray Analysis (CMA) have been clinically offered to children with Autism Spectrum Disorder(ASD). However, the actual utilization of these tests is low among parents of children with ASD. The aim of this study is to examine the association between parental perceptions regarding autism research and their intention to take their children to undergo recommended genomic tests. We conducted a web-based survey using a community strategy in Eastern North Carolina among parents of children with ASD. Our final sample constituted 204 parents. The majority were mothers, married and Caucasian. Parents' test intention was high among this sample, and those desiring to help and expressing favorable perceptions toward ASD genetic research were more likely to test. Our findings suggest a link between parental attitudes towards genetic research and their decision to test a child with ASD. This study can influence patient education approaches of health professionals in counseling parental genetic testing decision, as well as informing policy creation about access and outreach for parents toward ASD research.

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SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)

Cited by 681 publications

References 8 publications

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

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

MET Receptor Tyrosine Kinase Controls Dendritic Complexity, Spine Morphogenesis, and Glutamatergic Synapse Maturation in the Hippocampus

Can genetic research motivate parents to pursue genomic testing for children with autism spectrum disorder?

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