Human Gene Module / Chromosome 6 / SYNGAP1

SYNGAP1synaptic Ras GTPase activating protein 1

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
14 / 50
Rare Variants / Common Variants
144 / 0
Aliases
SYNGAP1, MRD5,  RASA1,  RASA5,  SYNGAP
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
6p21.32
Associated Disorders
EPS, EP, ID, ASD, DD/NDD
Relevance to Autism

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as intellectual disability and epilepsy (PMIDs 19196676, 20531469, 21237447, 23020937). Multiple LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23161826, 23708187, 26989088, 27525107, 28554332, 28708303). De novo LoF variants in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886) and in ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SYNGAP1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in SYNGAP1 were identified in an ASD proband from a cohort of 200 Canadian ASD trio families in PMID 27525107 and in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in PMID 27824329.

Molecular Function

A major component of the postsynaptic density (PSD)associated with NMDA receptors

Reports related to SYNGAP1 (50 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Kim MJ , et al. (2005) No -
2 Highly Cited Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Flavell SW , et al. (2006) No -
3 Highly Cited SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Rumbaugh G , et al. (2006) No -
4 Recent Recommendation Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. Hamdan FF , et al. (2009) No -
5 Recent Recommendation Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP. Muhia M , et al. (2010) No -
6 Support Functional impact of global rare copy number variation in autism spectrum disorders. Pinto D , et al. (2010) Yes -
7 Recent Recommendation A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation. Krepischi AC , et al. (2010) No -
8 Support A de novo paradigm for mental retardation. Vissers LE , et al. (2010) No -
9 Primary De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Hamdan FF , et al. (2011) Yes epilepsy
10 Recent Recommendation Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Hamdan FF , et al. (2011) No -
11 Recent Recommendation Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory. Lee KJ , et al. (2011) No -
12 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No Epilepsy, ASD
13 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
14 Recent Recommendation Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Berryer MH , et al. (2012) No ASD, Epilepsy
15 Support 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment. Writzl K and Knegt AC (2013) No Epilepsy
16 Recent Recommendation Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
17 Recent Recommendation SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity. Clement JP , et al. (2013) No -
18 Support Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Willsey AJ , et al. (2013) Yes -
19 Recent Recommendation SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. Wang CC , et al. (2014) No -
20 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ... Brett M , et al. (2014) Yes MCA
21 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
22 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
23 Support Recurrent de novo mutations implicate novel genes underlying simplex autism risk. O'Roak BJ , et al. (2014) Yes -
24 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
25 Recent Recommendation Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption... Kozol RA , et al. (2015) No -
26 Recent Recommendation De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Parker MJ , et al. (2015) No ASD, epilepsy/seizures
27 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
28 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
29 Support Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. Mignot C , et al. (2016) No ASD
30 Support Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern. Fieremans N , et al. (2016) No -
31 Support Mutations in HECW2 are associated with intellectual disability and epilepsy. Halvardson J , et al. (2016) Yes -
32 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
33 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
34 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No ASD, cognitive impairment
35 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
36 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
37 Support Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental traje... Prchalova D , et al. (2017) No Microcephaly, growth delay, behavioral problems, s
38 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No ASD, epilepsy/seizures
39 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Hamdan FF , et al. (2017) No DD/ID
40 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. Tumien B , et al. (2017) No -
41 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
42 Support Novel SYNGAP1 variant in a patient with intellectual disability and distinctive dysmorphisms. Kimura Y , et al. (2018) Yes -
43 Support Diagnostic value of partial exome sequencing in developmental disorders. Gieldon L , et al. (2018) No Microcephaly
44 Recent Recommendation SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. Michaelson SD , et al. (2018) No -
45 Recent Recommendation SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. Vlaskamp DRM , et al. (2018) No ASD
46 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop... Schluth-Bolard C , et al. (2019) No Behavioral abnormalities
47 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. Jiao Q , et al. (2019) No DD
48 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes. Xiong J , et al. (2019) Yes ID
49 Highly Cited SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Kim JH , et al. (1998) No -
50 Highly Cited A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Chen HJ , et al. (1998) No -
Rare Variants   (144)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 20531469 Pinto D , et al. (2010)
- - translocation De novo - - 30923172 Schluth-Bolard C , et al. (2019)
- - copy_number_loss De novo - Simplex 26079862 Parker MJ , et al. (2015)
- p.Trp267Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
- - copy_number_loss De novo - Simplex 20683986 Krepischi AC , et al. (2010)
- - copy_number_loss Unknown - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.840C>G p.Tyr280Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.490C>T p.Arg164Ter stop_gained De novo - - 28708303 Chrot E , et al. (2017)
c.490C>T p.Arg164Ter stop_gained De novo - - 31031587 Xiong J , et al. (2019)
c.763-1G>A - splice_site_variant De novo - - 30091983 Gieldon L , et al. (2018)
c.2215+1G>C p.? splice_site_variant De novo - - 30945278 Jiao Q , et al. (2019)
c.3190C>T p.Gln1064Ter stop_gained De novo - - 28708303 Chrot E , et al. (2017)
c.389-2A>T - splice_site_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.427C>T p.Arg143Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
delTT - frameshift_variant De novo - Simplex 24267886 Willsey AJ , et al. (2013)
delC - frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2104C>T p.Gln702Ter stop_gained Unknown - - 23708187 Carvill GL , et al. (2013)
c.1676+2T>C p.? splice_site_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.509G>A p.Arg170Gln missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.583G>C p.Ala195Pro missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.1676+5G>A p.? splice_site_variant De novo - - 28576131 Prchalova D , et al. (2017)
c.403C>T p.Arg135Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.427C>T p.Arg143Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.490C>T p.Arg164Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.510-1G>A - splice_site_variant De novo - Simplex 23033978 de Ligt J , et al. (2012)
c.1630C>T p.Arg544Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.1995T>A p.Tyr665Ter stop_gained Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.2197C>T p.Gln733Ter stop_gained De novo - Simplex 29346770 Takata A , et al. (2018)
c.412A>T p.Lys138Ter stop_gained De novo - Simplex 19196676 Hamdan FF , et al. (2009)
c.412A>T p.Lys138Ter stop_gained De novo - Simplex 21376300 Hamdan FF , et al. (2011)
c.2294+1G>A - splice_site_variant De novo - Simplex 21237447 Hamdan FF , et al. (2011)
- p.Lys108ValfsTer25 frameshift_variant Unknown - - 23708187 Carvill GL , et al. (2013)
- - copy_number_loss Apparently de novo - Simplex 23687080 Writzl K and Knegt AC (2013)
- - copy_number_loss De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.823delC p.Pro275Profs frameshift_variant De novo - - 31031587 Xiong J , et al. (2019)
c.3200delC p.Pro1067fs frameshift_variant De novo - - 29286531 Tumien B , et al. (2017)
c.509+1G>T p.? splice_site_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.1735C>T p.Arg579Ter stop_gained De novo - Simplex 19196676 Hamdan FF , et al. (2009)
c.1735C>T p.Arg579Ter stop_gained De novo - Simplex 21376300 Hamdan FF , et al. (2011)
c.91C>T p.Arg31Ter stop_gained De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.3408+1G>A p.? splice_site_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.3748C>T p.Gln1250Ter stop_gained De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.3494C>T p.Ser1165Leu missense_variant Unknown - - 27159028 Fieremans N , et al. (2016)
c.1081C>T p.Gln361Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2899C>T p.Arg967Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.403C>T p.Arg135Ter stop_gained De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.1366C>T p.Gln456Ter stop_gained De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1735C>T p.Arg579Ter stop_gained De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.2059C>T p.Arg687Ter stop_gained De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.2899C>T p.Arg967Ter stop_gained De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.2899C>T p.Arg967Ter stop_gained Unknown - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.829dupC p.Pro277ProfsTer7 frameshift_variant De novo - - 26544041 Zhang Y , et al. (2015)
c.1685C>T p.Pro562Leu missense_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.1741C>T p.Arg581Trp missense_variant De novo - Simplex 29381230 Kimura Y , et al. (2018)
c.387G>A p.(=) splice_site_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.190-2A>G p.? splice_site_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.388-2A>T p.? splice_site_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.698G>A p.Cys233Tyr missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.140G>A p.Arg47Gln missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3344T>C p.Ile1115Thr missense_variant Unknown - Unknown 19196676 Hamdan FF , et al. (2009)
c.1084T>C p.Trp362Arg missense_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
c.1685C>T p.Pro562Leu missense_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
c.423G>C p.Leu141Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.425A>T p.Lys142Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3134C>G p.Ala1045Gly missense_variant Unknown Not tested - 24690944 Brett M , et al. (2014)
c.3826dup p.Asp1276GlyfsTer7 frameshift_variant De novo - - 30091983 Gieldon L , et al. (2018)
c.3055C>T p.Arg1019Cys missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.2444G>A p.Arg815His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.603T>G p.Asp201Glu missense_variant Unknown - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.844T>C p.Cys282Arg missense_variant Unknown - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.68-1518-?_1530_?del p.? copy_number_loss De novo - Simplex 26989088 Mignot C , et al. (2016)
c.2677delC p.Gln893Ter frameshift_variant De novo - Simplex 21237447 Hamdan FF , et al. (2011)
c.1030G>A p.Gly344Ser missense_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1250A>G p.Tyr417Cys missense_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1797C>G p.Cys599Trp missense_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1889T>A p.Ile630Asn missense_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.2533G>T p.Asp845Tyr missense_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.348C>A p.Tyr116Ter stop_gained De novo - Extended multiplex 26989088 Mignot C , et al. (2016)
c.2438delT p.Leu813Argfs frameshift_variant De novo - Simplex 19196676 Hamdan FF , et al. (2009)
c.2438delT p.Leu813Argfs frameshift_variant De novo - Simplex 21376300 Hamdan FF , et al. (2011)
c.1677-2_1685del p.? splice_site_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
- - copy_number_loss De novo - Multiplex (monozygotic twins) 30541864 Vlaskamp DRM , et al. (2018)
c.828dup p.Lys277GlnfsTer7 frameshift_variant Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.2630dup p.Thr878AspfsTer60 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
GAAGdel321-324 p.Lys108Ter frameshift_variant De novo - Simplex 21237447 Hamdan FF , et al. (2011)
c.3583-6G>A p.Val1195AlafsTer27 splice_site_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.2933del p.Pro978HisfsTer99 frameshift_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.2212_2213del p.Ser738Ter frameshift_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
c.427C>T p.Arg143Ter stop_gained De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.490C>T p.Arg164Ter stop_gained De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.3406dup p.Gln1136ProfsTer17 frameshift_variant Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.1057delC p.Leu353TrpfsTer13 frameshift_variant Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.333delA p.Lys114SerfsTer20 frameshift_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.3682_3685del p.Glu1228fs frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1515C>G p.Tyr505Ter stop_gained De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.1970G>A p.Trp657Ter stop_gained Unknown - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.2059C>T p.Arg687Ter stop_gained De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.1782delC p.Leu595CysfsTer55 frameshift_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.310C>T p.Arg104Cys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3505G>T p.Glu1169Ter stop_gained De novo - Extended multiplex 30541864 Vlaskamp DRM , et al. (2018)
c.3718C>T p.Arg1240Ter stop_gained De novo - Extended multiplex 30541864 Vlaskamp DRM , et al. (2018)
c.3657T>G p.Tyr1219Ter stop_gained De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.3583-6G>A p.Val1195AlafsTer27 splice_site_variant De novo - Simplex 25167861 Redin C , et al. (2014)
c.455_459del p.Arg152GlnfsTer14 frameshift_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.3788_3794delTTGGCAG p.Ile1263Serfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.2184delC p.Asn729ThrfsTer31 frameshift_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
c.998_999del p.Val333AlafsTer frameshift_variant De novo - Simplex 21076407 Vissers LE , et al. (2010)
c.1288C>T p.Leu430Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2492G>C p.Arg831Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.639delC p.Ile214TrpfsTer9 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.3545del p.Glu1182GlyfsTer14 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.1253_1254del p.Lys418ArgfsTer54 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.3445C>T p.Arg1149Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.333delA p.Lys114SerfsTer20 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.690dupC p.Phe231LeufsTer14 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1393delC p.Leu465PhefsTer9 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.121C>T p.Arg41Cys missense_variant Unknown - Extended multiplex 30541864 Vlaskamp DRM , et al. (2018)
c.2214_2217del p.Glu739GlyfsTer20 frameshift_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.968T>C p.Leu323Pro missense_variant De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.1210G>C p.Ala404Pro missense_variant De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.822_823insC p.Lys277GlnfsTer7 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.3959C>A p.Pro1320His missense_variant Unknown - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.[insA;delCTGGT] - frameshift_variant;frameshift_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.252_253delCA p.Thr85SerfsTer14 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.435_447dup p.Leu150ValfsTer6 frameshift_variant De novo - Multiplex 30541864 Vlaskamp DRM , et al. (2018)
c.283dupC p.His95ProfsTer5 frameshift_variant Familial Paternal Simplex 23161826 Berryer MH , et al. (2012)
c.424_427delAAAC p.Lys142GlufsTer31 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.2177_2180delGGAA p.Arg726ThrfsTer33 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1081T>C p.Leu327Pro missense_variant De novo - Multiplex (monozygotic twins) 26079862 Parker MJ , et al. (2015)
c.1390delinsTTCC p.Leu465dup inframe_insertion De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.1463delC p.Thr488SerfsTer7 frameshift_variant De novo - Extended multiplex 30541864 Vlaskamp DRM , et al. (2018)
c.877C>T p.Arg293Cys missense_variant Unknown Not maternal Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.3406dupC p.Gln1136ProfsTer17 frameshift_variant De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.1726_1730delinsGGCTGC p.Glu578AlafsTer74 frameshift_variant De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1388_1393delACTTCC p.Asp463_Leu465delinsVal inframe_deletion De novo - Simplex 30541864 Vlaskamp DRM , et al. (2018)
c.1167_1168delAG p.Gly391GlnfsTer27 frameshift_variant De novo - Extended multiplex 30541864 Vlaskamp DRM , et al. (2018)
c.3235C>T p.Gln1079Ter stop_gained De novo - Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
c.2722C>T p.Arg922Ter (p.Arg908Ter) stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2740C>T p.Gln928Ter (p.Gln914Ter) stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2936_2938delinsCA p.Phe979SerfsTer98 frameshift_variant De novo - Multi-generational 30541864 Vlaskamp DRM , et al. (2018)
c.509G>A p.Arg170Gln missense_variant De novo - Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
c.1550_1555delTGTATGinsTG p.Tyr518AsnfsTer8 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2732delT p.Leu925Ter (p.Leu911ProfsTer152) frameshift_variant De novo - Multiplex 25533962 Deciphering Developmental Disorders Study (2014)
c.425_434delAACGAACGAAinsAACGAA p.Thr144SerfsTer29 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

1S

Score Delta: Score remained at 1.1 + S

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2017
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as intellectual disability and epilepsy (PMIDs 19196676, 20531469, 21237447, 23020937). Multiple LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23161826, 23708187, 26989088, 27525107, 28554332, 28708303). De novo LoF variants in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886) and in ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SYNGAP1 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in SYNGAP1 were identified in an ASD proband from a cohort of 200 Canadian ASD trio families in PMID 27525107 and in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in PMID 27824329.

7/1/2017
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as intellectual disability and epilepsy (PMIDs 19196676, 20531469, 21237447, 23020937). Multiple LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23161826, 23708187, 26989088, 27525107, 28554332, 28708303). De novo LoF variants in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886) and in ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SYNGAP1 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in SYNGAP1 were identified in an ASD proband from a cohort of 200 Canadian ASD trio families in PMID 27525107 and in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in PMID 27824329.

4/1/2017
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Functional impact of global rare copy number variation in autism spectrum disorders.2010] [De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.2011] [Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [A de novo paradigm for mental retardation.2010] [Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.2011] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.2012] [6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment.2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.2009] [A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation.2010] [SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family.1998] [A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.1998] [Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking.2005] [Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number.2006] [SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons.2006] [Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.2010] [Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity.2013] [SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks.2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.2016] [Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern.2016] [Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [Genome-wide characteristics of de novo mutations in autism.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental traje...2017]
1/1/2017
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

10/1/2016
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

7/1/2016
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

4/1/2016
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Functional impact of global rare copy number variation in autism spectrum disorders.2010] [De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.2011] [Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.2011] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.2012] [6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment.2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.2009] [A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation.2010] [SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family.1998] [A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.1998] [Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking.2005] [Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number.2006] [SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons.2006] [Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.2010] [Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity.2013] [SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks.2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.2016] [Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern.2016]
1/1/2016
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Functional impact of global rare copy number variation in autism spectrum disorders.2010] [De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.2011] [Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.2011] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.2012] [6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment.2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.2009] [A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation.2010] [SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family.1998] [A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.1998] [Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking.2005] [Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number.2006] [SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons.2006] [Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.2010] [Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity.2013] [SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks.2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

Reports Added
[Functional impact of global rare copy number variation in autism spectrum disorders.2010] [De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.2011] [Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.2011] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.2012] [6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment.2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.2009] [A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation.2010] [SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family.1998] [A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.1998] [Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking.2005] [Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number.2006] [SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons.2006] [Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.2010] [Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity.2013] [SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks.2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.2015]
4/1/2015
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

1/1/2015
1S
icon
1S

Score remained at 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

10/1/2014
2S
icon
1S

Decreased from 2S to 1S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SYNGAP1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2014
No data
icon
2S

Increased from No data to 2S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports.

4/1/2014
No data
icon
2S

Increased from No data to 2S

Description

Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as mental retardation and intellectual disability (e.g., PMID 21237447). More recently, an additional eight de novo LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23708187, and 23161826). A de novo LoF variant in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886). However, a rigorous statistical comparison with controls was not performed in these reports.

Krishnan Probability Score

Score 0.49441785940172

Ranking 3673/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999844974797

Ranking 327/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.991

Ranking 24/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 3.7250329634198E-7

Ranking 5/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 133

Ranking 4/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
CNVs associated with SYNGAP1(1 CNVs)
6p21.32 23 Deletion-Duplication 34  /  266
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