Human Gene Module / Chromosome X / IQSEC2

IQSEC2IQ motif and Sec7 domain 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
13 / 51
Rare Variants / Common Variants
155 / 0
Aliases
IQSEC2, RP11-258C19.1,  BRAG1,  MRX1
Associated Syndromes
-
Chromosome Band
Xp11.22
Associated Disorders
SCZ, DD/NDD, ADHD, ID, EPS, ASD
Relevance to Autism

Autistic features were observed in some affected individuals with intellectual diability caused by IQSEC2 mutations (Shoubridge et al., 2010; Tran Mau-Them et al., 2013).

Molecular Function

This gene encodes a guanine nucleotide exchange factor for the ARF family of small GTP-binding proteins. The encoded protein is a component of the postsynaptic density at excitatory synapses, and may play a critical role in cytoskeletal and synaptic organization through the activation of selected ARF substrates including ARF1 and ARF6. Mutations in this gene are a cause of Mental retardation, X-linked 1 (MRX1) [MIM:309530], a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to IQSEC2 (51 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability Shoubridge C , et al. (2010) No -
2 Support Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability Tran Mau-Them F , et al. (2013) No Epilepsy/seizures
3 Positive Association De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
4 Support Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for genetic counseling and clinical diagnosis Gandomi SK , et al. (2013) No Autistic features
5 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
6 Support Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome Olson HE , et al. (2015) No -
7 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities Zhang Y , et al. (2015) No -
8 Support A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability Madrigal I , et al. (2016) No -
9 Support Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family Kalscheuer VM , et al. (2016) No ASD, epilepsy/seizures
10 Recent Recommendation Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression Brown JC , et al. (2016) No -
11 Support De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016) No DD, ID
12 Support The molecular and phenotypic spectrum of IQSEC2-related epilepsy Zerem A , et al. (2016) No -
13 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, microcephaly
14 Support Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy Ewans LJ , et al. (2017) No -
15 Support The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey Helm BM , et al. (2017) No ASD
16 Support Developmental progression of intellectual disability, autism, and epilepsy in a child with an IQSEC2 gene mutation Zipper R , et al. (2017) Yes Developmental regression
17 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
18 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
19 Recent recommendation IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients Mignot C , et al. (2018) No Autistic behavior
20 Support Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype Radley JA , et al. (2019) No ASD, epilepsy/seizures
21 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
22 Support An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors Rogers EJ , et al. (2019) No -
23 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
24 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
25 Support Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene Barrie ES , et al. (2019) No ASD, ADHD
26 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability Ibarluzea N , et al. (2020) No -
27 Support Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder Accogli A et al. (2020) No DD, SCZ, learning disability, psychosis, stereotyp
28 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
29 Support Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy Wayhelova M et al. (2020) No DD, ID, epilepsy/seizures, Afs, stereotypy
30 Support - Lopergolo D et al. (2021) No ASD, epilepsy/seizures
31 Support - Alonso-Gonzalez A et al. (2021) Yes -
32 Support - Abe-Hatano C et al. (2021) No -
33 Support - Chen JS et al. (2021) Yes -
34 Support - Valentino F et al. (2021) No -
35 Support - Trakadis Y et al. (2021) No DD
36 Support - Brant B et al. (2021) No -
37 Support - Mahjani B et al. (2021) Yes -
38 Support - Mosallaei M et al. (2022) No -
39 Support - Álvarez-Mora MI et al. (2022) No -
40 Support - Brea-Fernández AJ et al. (2022) No -
41 Support - Shoubridge C et al. (2022) No ASD
42 Support - Chuan Z et al. (2022) No DD
43 Support - Hu C et al. (2022) Yes -
44 Support - Krgovic D et al. (2022) Yes DD, epilepsy/seizures
45 Support - Chen Y et al. (2021) Yes -
46 Support - Zhou X et al. (2022) Yes -
47 Support - Liu X et al. (2022) No ASD, stereotypy
48 Support - Spataro N et al. (2023) No Epilepsy/seizures, autistic features
49 Support - Ko YJ et al. (2023) No ASD
50 Support - et al. () Yes -
51 Support - et al. () No -
Rare Variants   (155)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - - 33368194 Lopergolo D et al. (2021)
- - copy_number_loss De novo - - 33368194 Lopergolo D et al. (2021)
- - copy_number_gain De novo - - 23674175 Tran Mau-Them F , et al. (2013)
c.3679C>T p.Gln1227Ter stop_gained De novo - Simplex 38200111 et al. ()
c.316C>T p.Gln106Ter stop_gained De novo - - 36267700 Liu X et al. (2022)
c.1417G>T p.Glu473Ter stop_gained De novo - - 36267700 Liu X et al. (2022)
c.3016-1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.256G>T p.Glu86Ter stop_gained Unknown - - 35571021 Chuan Z et al. (2022)
c.1638G>A p.Trp546Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.97C>T p.Gln33Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.184C>T p.Arg62Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.738-1G>C - splice_site_variant De novo - - 30206421 Mignot C , et al. (2018)
c.883C>T p.Arg295Trp missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.2317C>T p.Leu773Phe stop_gained De novo - - 28815955 Helm BM , et al. (2017)
c.3277+2T>G - splice_site_variant De novo - - 30206421 Mignot C , et al. (2018)
c.3016-1G>A - splice_site_variant Unknown - - 34615535 Mahjani B et al. (2021)
- - copy_number_gain De novo - Simplex 23674175 Tran Mau-Them F , et al. (2013)
c.1510C>T p.Gln504Ter stop_gained Unknown - - 30206421 Mignot C , et al. (2018)
c.2272C>T p.Arg758Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.2317C>T p.Gln773Ter stop_gained Unknown - - 30206421 Mignot C , et al. (2018)
c.2776C>T p.Arg926Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.2854C>T p.Gln952Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.2962C>T p.Gln988Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.2563C>T p.Arg855Ter stop_gained De novo - - 35813072 Krgovic D et al. (2022)
c.2203C>T p.Gln735Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.267C>G p.Tyr89Ter stop_gained De novo - - 33368194 Lopergolo D et al. (2021)
c.1075C>T p.Arg359Cys missense_variant De novo - - 36267700 Liu X et al. (2022)
c.936G>C p.Glu312Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3163C>T p.Arg1055Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.3163C>T p.Arg1055Ter stop_gained Unknown - - 30206421 Mignot C , et al. (2018)
c.3278C>A p.Ser1093Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.3387C>A p.Tyr1129Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.3433C>T p.Arg1145Ter stop_gained De novo - - 30206421 Mignot C , et al. (2018)
c.3278-329dup - frameshift_variant De novo - - 27864847 Parrini E , et al. (2016)
c.3235T>C p.Ser1079Pro missense_variant De novo - - 36267700 Liu X et al. (2022)
c.1639G>A p.Ala547Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2717T>C p.Met906Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1591C>T p.Arg531Ter stop_gained De novo - - 33368194 Lopergolo D et al. (2021)
c.2911C>T p.Arg971Ter stop_gained De novo - - 33368194 Lopergolo D et al. (2021)
c.4419dup p.Ser1474GlnfsTer133 frameshift_variant Unknown - - 37943464 et al. ()
c.3065G>A p.Arg1022His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.513C>G p.Gly171%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3859C>T p.Gln1287Ter stop_gained De novo - - 33368194 Lopergolo D et al. (2021)
c.2678C>T p.Thr893Ile missense_variant De novo - - 28815955 Helm BM , et al. (2017)
c.-134_-132del - inframe_deletion De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.1049C>T p.Ala350Val missense_variant De novo - - 29026562 Zipper R , et al. (2017)
c.2278G>A p.Gly760Ser missense_variant De novo - - 30206421 Mignot C , et al. (2018)
c.2312G>A p.Gly771Asp missense_variant De novo - - 30206421 Mignot C , et al. (2018)
c.2354C>T p.Pro785Leu missense_variant De novo - - 30206421 Mignot C , et al. (2018)
c.1075C>T p.Arg359Cys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
- - copy_number_gain Familial Maternal Multiplex 33368194 Lopergolo D et al. (2021)
c.737+10385del - intron_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.3463C>T p.Arg1155Trp missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.3097C>T p.Gln1033Ter stop_gained De novo - Simplex 25167861 Redin C , et al. (2014)
c.3576C>T p.Tyr1192= stop_gained De novo - Simplex 30666632 Radley JA , et al. (2019)
c.2582+2T>C - splice_site_variant De novo - Simplex 31415821 Barrie ES , et al. (2019)
c.804del p.Tyr269ThrfsTer3 frameshift_variant De novo - - 36267700 Liu X et al. (2022)
c.826C>G p.Pro276Ala missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.856G>A p.Ala286Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3277+5G>A - splice_site_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.1591C>T p.Arg531Trp stop_gained De novo - Simplex 30666632 Radley JA , et al. (2019)
c.2272C>T p.Arg758Ter stop_gained De novo - Simplex 31406558 Munnich A , et al. (2019)
c.3011T>C p.Leu1004Pro missense_variant De novo - - 33368194 Lopergolo D et al. (2021)
c.2857G>A p.Ala953Thr missense_variant Unknown - - 35347702 Shoubridge C et al. (2022)
c.3576C>T p.Tyr1192= stop_gained De novo - Multiplex 30666632 Radley JA , et al. (2019)
c.3030C>G p.Phe1010Leu missense_variant Unknown - - 35347702 Shoubridge C et al. (2022)
c.3206G>A p.Arg1069Gln missense_variant Unknown - - 35347702 Shoubridge C et al. (2022)
c.3322C>T p.Gln1108Ter stop_gained De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.1401+2T>G - splice_site_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.804del p.Tyr269ThrfsTer3 frameshift_variant De novo - - 28815955 Helm BM , et al. (2017)
c.999+8A>G - splice_region_variant Familial Maternal - 33368194 Lopergolo D et al. (2021)
c.804del p.Tyr269ThrfsTer3 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.3433C>T p.Arg1145Ter stop_gained Unknown Not maternal - 30206421 Mignot C , et al. (2018)
c.854del p.Pro285LeufsTer21 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.3065G>A p.Arg1022His missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.2507C>T p.Ala836Val missense_variant De novo - Simplex 30666632 Radley JA , et al. (2019)
c.2561_2575del p.Glu854_Glu858del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.2752G>T p.Val918Phe missense_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.2078del p.Gly693ValfsTer29 frameshift_variant Unknown - - 30206421 Mignot C , et al. (2018)
c.2292del p.Phe764LeufsTer12 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.51_61del p.Asn17LysfsTer62 frameshift_variant De novo - - 25914188 Olson HE , et al. (2015)
c.1170dup p.Gln391AlafsTer5 frameshift_variant De novo - - 34363551 Trakadis Y et al. (2021)
c.3412G>C p.Gly1138Arg missense_variant De novo - Simplex 30666632 Radley JA , et al. (2019)
c.2582G>C p.Ser861Thr missense_variant De novo - Simplex 24306141 Gandomi SK , et al. (2013)
c.-94G>C - missense_variant Familial Maternal Multiplex 31906484 Ibarluzea N , et al. (2020)
c.2563C>T p.Arg855Ter stop_gained De novo - Simplex 23674175 Tran Mau-Them F , et al. (2013)
c.3206G>C p.Arg1069Pro missense_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.3079del p.Leu1027SerfsTer75 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.4039dup p.Ala1347GlyfsTer40 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.3415G>A p.Ala1139Thr missense_variant Unknown - Multiplex 30206421 Mignot C , et al. (2018)
c.1885del p.His629MetfsTer4 frameshift_variant De novo - - 33368194 Lopergolo D et al. (2021)
c.2139del p.Gly714AlafsTer8 frameshift_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.3457del p.Arg1153GlyfsTer244 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.738-1G>A - splice_site_variant Familial Maternal Multiplex 30206421 Mignot C , et al. (2018)
c.588_610del p.Arg197AlafsTer34 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.1076_1078del p.Arg359del inframe_deletion Unknown - Simplex 31130284 Monies D , et al. (2019)
c.2909G>A p.Arg970His missense_variant Familial Maternal - 35347702 Shoubridge C et al. (2022)
c.1211del p.Ala404GlyfsTer65 frameshift_variant Unknown - Unknown 35873028 Chen Y et al. (2021)
c.854del p.Pro285LeufsTer21 frameshift_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.1405_1406del p.Lys469ValfsTer4 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.1744_1763del p.Arg582CysfsTer9 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.3613del p.Leu1205TrpfsTer192 frameshift_variant De novo - - 33368194 Lopergolo D et al. (2021)
c.3780del p.Gln1261SerfsTer136 frameshift_variant De novo - - 33368194 Lopergolo D et al. (2021)
c.3780del p.Gln1261SerfsTer136 frameshift_variant De novo - - 34356170 Valentino F et al. (2021)
c.3005A>G p.Asp1002Gly missense_variant Familial Maternal - 35347702 Shoubridge C et al. (2022)
c.1849del p.Arg617AlafsTer16 frameshift_variant Familial Maternal - 36267700 Liu X et al. (2022)
c.918_922dup p.Gln308ArgfsTer8 frameshift_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.1983_1999del p.Leu662GlnfsTer25 frameshift_variant Unknown - - 30206421 Mignot C , et al. (2018)
c.2317_2332del p.Gln773GlyfsTer25 frameshift_variant Unknown - - 30206421 Mignot C , et al. (2018)
c.2507C>T p.Ala836Val missense_variant Familial Maternal Simplex 28815955 Helm BM , et al. (2017)
c.55_151delinsAT p.Ala19IlefsTer32 frameshift_variant De novo - - 30206421 Mignot C , et al. (2018)
c.1170dup p.Gln391AlafsTer5 frameshift_variant De novo - Simplex 32529990 Accogli A et al. (2020)
c.804del p.Tyr269ThrfsTer3 frameshift_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.3817C>T p.Gln1273Ter stop_gained Familial Maternal Multiplex 31415821 Barrie ES , et al. (2019)
c.2278G>A p.Gly760Ser missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.2983C>T p.Arg995Trp missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.2052_2053del p.Cys684Ter frameshift_variant De novo - Simplex 24306141 Gandomi SK , et al. (2013)
c.1049C>A p.Pro350His missense_variant Familial Maternal Multiplex 26544041 Zhang Y , et al. (2015)
c.2117A>G p.Asn706Ser missense_variant Familial Maternal Simplex 30666632 Radley JA , et al. (2019)
c.4110_4111del p.Tyr1371GlnfsTer15 frameshift_variant De novo - - 33368194 Lopergolo D et al. (2021)
c.4419_4431del p.Ser1474ArgfsTer17 frameshift_variant De novo - - 33368194 Lopergolo D et al. (2021)
c.4126_4127dup p.Gln1376HisfsTer22 frameshift_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.913del p.Leu305Ter frameshift_variant Unknown - Multi-generational 30763456 Zhou WZ , et al. (2019)
c.4419del p.Ser1474ValfsTer21 frameshift_variant De novo - Simplex 31415821 Barrie ES , et al. (2019)
c.854del p.Pro285LeufsTer21 frameshift_variant De novo - Simplex 33624935 Abe-Hatano C et al. (2021)
c.443_444insCA p.Ala149LysfsTer58 frameshift_variant Familial Maternal - 36267700 Liu X et al. (2022)
c.3116-3_3116-2del - splice_site_variant Familial Maternal - 35183220 Álvarez-Mora MI et al. (2022)
c.2529_2535del p.His843GlnfsTer62 frameshift_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.104delinsGC p.Gln35ArgfsTer48 frameshift_variant De novo - Simplex 30666632 Radley JA , et al. (2019)
c.1076G>A p.Arg359His missense_variant Familial Maternal Multiplex 33368194 Lopergolo D et al. (2021)
c.849_850insG p.Pro284AlafsTer41 frameshift_variant De novo - Multiplex 32530565 Suzuki T et al. (2020)
c.3364C>T p.Arg1122Cys missense_variant Familial Maternal Multiplex 35174982 Mosallaei M et al. (2022)
c.4401del p.Gly1468AlafsTer27 frameshift_variant Unknown Not maternal - 30206421 Mignot C , et al. (2018)
c.280C>T;c.895C>T p.Gln94Ter;p.Gln299Ter stop_gained De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.1240_1243del p.Asp414ArgfsTer54 frameshift_variant De novo - Simplex 30666632 Radley JA , et al. (2019)
c.2507C>T p.Ala836Val missense_variant Unknown Not maternal Multiplex 31415821 Barrie ES , et al. (2019)
c.1567_2199delinsGGC p.Thr523_Thr733delinsGly inframe_deletion De novo - - 30206421 Mignot C , et al. (2018)
c.626_627delinsT p.Ala209ValfsTer48 frameshift_variant De novo - Simplex 30666632 Radley JA , et al. (2019)
c.737+12259_737+12311del - splice_site_variant Unknown Not maternal Simplex 28815955 Helm BM , et al. (2017)
c.770G>A p.Ser257Asn missense_variant Familial Maternal Extended multiplex 32529990 Accogli A et al. (2020)
c.3463C>T p.Arg1155Trp missense_variant Familial Maternal Multi-generational 30206421 Mignot C , et al. (2018)
c.4419dup p.Ser1474GlnfsTer133 frameshift_variant Familial Maternal Multiplex 30666632 Radley JA , et al. (2019)
c.4204G>A p.Ala1402Thr missense_variant Familial Maternal Multi-generational 33368194 Lopergolo D et al. (2021)
c.3116-3_3116-2del - splice_site_variant Familial Maternal Multi-generational 26733290 Madrigal I , et al. (2016)
c.1075C>T p.Arg359Cys missense_variant Familial Maternal Multi-generational 20473311 Shoubridge C , et al. (2010)
c.2273G>A p.Arg758Gln missense_variant Familial Maternal Multi-generational 20473311 Shoubridge C , et al. (2010)
c.2402A>C p.Gln801Pro missense_variant Familial Maternal Multi-generational 20473311 Shoubridge C , et al. (2010)
c.2587C>T p.Arg863Trp missense_variant Familial Maternal Multi-generational 20473311 Shoubridge C , et al. (2010)
c.2366C>T p.Ala789Val missense_variant Familial Maternal Multi-generational 26793055 Kalscheuer VM , et al. (2016)
c.1813_1814del p.Asp605ProfsTer3 frameshift_variant Familial Maternal Multiplex 32564198 Wayhelova M et al. (2020)
c.4335_4399del p.His1446TrpfsTer139 frameshift_variant Unknown Not maternal Simplex 28815955 Helm BM , et al. (2017)
c.2548C>T;c.3163C>T p.Arg850Ter;p.Arg1055Ter stop_gained Familial Maternal Simplex 29100083 Hamdan FF , et al. (2017)
c.2679_2680insA p.Asp894ArgfsTer10 frameshift_variant De novo (germline mosaicism) - Multiplex 28295038 Ewans LJ , et al. (2017)
c.4418_4419insG p.Ser1474GlnfsTer133 frameshift_variant De novo - Multiplex (monozygotic twins) 30666632 Radley JA , et al. (2019)
c.2203C>T p.Gln735Ter stop_gained De novo - - 27476654 Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

S

Syndromic

See all Category S Genes

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."

4/1/2021
1
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1

Score remained at 1

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[Comorbidities associated with genetic abnormalities in children with intellectual disability2021]
1/1/2021
1
icon
1

Score remained at 1

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?2021] [Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021] [Whole genome sequencing of 45 Japanese patients with intellectual disability2021]
7/1/2020
1
icon
1

Score remained at 1

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder2020] [A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020] [Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[New Scoring Scheme]
7/1/2019
4S
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4S

Decreased from 4S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019] [Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene.2019]
4/1/2019
4S
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4S

Decreased from 4S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors.2019]
1/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males). Radley et al., 2019 reported 14 novel patients with IQSEC2 variants and found that autism was present in 5 cases (35.7%), while stereotypies were present in 10 cases (71.4%).

Reports Added
[Deep phenotyping of fourteen new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype.2019] [Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
10/1/2018
4S
icon
4S

Decreased from 4S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016). A comparative study involving 37 unpublished patients (18 males, 19 females) with pathogenic IQSEC2 variants, in addition to five patients previously reported with IQSEC2 variants but without corresponding clinical data, in Mignot et al., 2018 determined that autistic behaviors were observed in 20 patients (8 females and 12 males).

Reports Added
[IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.2018]
10/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016).

Reports Added
[Developmental progression of intellectual disability, autism, and epilepsy in a child with an IQSEC2 gene mutation.2017] [High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]
7/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016).

Reports Added
[The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey.2017]
4/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016).

Reports Added
[De novo mutations in epileptic encephalopathies.2013] [Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability.2010] [Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability.2013] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability.2016] [Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for ...2013] [Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family.2016] [Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.2015] [Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression.2016] [De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies.2016] [The molecular and phenotypic spectrum of IQSEC2-related epilepsy.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy.2017]
1/1/2017
S
icon
4S

Increased from S to 4S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016). Targeted resequencing using a 95-gene panel in 349 patients with drug-resistant epilepsies identified a de novo frameshift variant in IQSEC2 in a female proband presenting with autism spectrum disorder, childhood onset epileptic encephalopathy, and microcephaly (Parrini et al., 2016).

Reports Added
[Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016]
10/1/2016
icon
S

Increased from to S

Description

Mutations in IQSEC2 are responsible for a form of X-linked intellectual disability (MRX1; OMIM 309530); epilepsy and autistic features have been observed in some affected individuals with IQSEC2-mediated intellectual disability (Shoubridge et al., 2010; Tran Mau-Them et al., 2013; Gandomi et al., 2014; Madrigal et al., 2016; Kalscheuer et al., 2016). Phenotypic evaluation of 18 patients with epilepsy and intellectual disability caused by IQSEC2 variants, including 15 previously reported cases and 3 novel cases, found that 6 out of 12 cases with de novo IQSEC2 variants presented with autistic features and/or stereotypic hand movements (Zerem et al., 2016).

Reports Added
[The molecular and phenotypic spectrum of IQSEC2-related epilepsy.2016]
Krishnan Probability Score

Score 0.49114483778822

Ranking 5762/25841 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.
Original Source
ExAC Score

Score 0.97539047920439

Ranking 2250/18225 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
Original Source
Sanders TADA Score

Score 0.94230474587916

Ranking 15256/18665 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).
Original Source
Zhang D Score

Score 0.46168558645023

Ranking 815/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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