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
7 / 33
Rare Variants / Common Variants
114 / 0
Aliases
IQSEC2, RP11-258C19.1,  BRAG1,  MRX1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
Xp11.22
Associated Disorders
DD/NDD, ADHD, EPS, ASD, ID, SCZ
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.

Reports related to IQSEC2 (33 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 -
Rare Variants   (114)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo NA - 33368194 Lopergolo D et al. (2021)
- - copy_number_loss De novo NA - 33368194 Lopergolo D et al. (2021)
- - copy_number_gain De novo NA - 23674175 Tran Mau-Them F , et al. (2013)
c.97C>T p.Gln33Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.184C>T p.Arg62Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.1510C>T p.Gln504Ter stop_gained Unknown - - 30206421 Mignot C , et al. (2018)
c.2317C>T p.Gln773Ter stop_gained Unknown - - 30206421 Mignot C , et al. (2018)
c.738-1G>C - splice_site_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.2317C>T p.Leu773Phe stop_gained De novo NA - 28815955 Helm BM , et al. (2017)
c.3163C>T p.Arg1055Ter stop_gained Unknown - - 30206421 Mignot C , et al. (2018)
c.3277+2T>G - splice_site_variant De novo NA - 30206421 Mignot C , et al. (2018)
- - copy_number_gain De novo NA Simplex 23674175 Tran Mau-Them F , et al. (2013)
c.2272C>T p.Arg758Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.2776C>T p.Arg926Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.2854C>T p.Gln952Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.2962C>T p.Gln988Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.267C>G p.Tyr89Ter stop_gained De novo NA - 33368194 Lopergolo D et al. (2021)
c.3163C>T p.Arg1055Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.3278C>A p.Ser1093Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.3387C>A p.Tyr1129Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.3433C>T p.Arg1145Ter stop_gained De novo NA - 30206421 Mignot C , et al. (2018)
c.3278-329dup - frameshift_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.1591C>T p.Arg531Ter stop_gained De novo NA - 33368194 Lopergolo D et al. (2021)
c.2911C>T p.Arg971Ter stop_gained De novo NA - 33368194 Lopergolo D et al. (2021)
c.3859C>T p.Gln1287Ter stop_gained De novo NA - 33368194 Lopergolo D et al. (2021)
- - copy_number_gain Familial Maternal Multiplex 33368194 Lopergolo D et al. (2021)
c.2678C>T p.Thr893Ile missense_variant De novo NA - 28815955 Helm BM , et al. (2017)
c.737+10385del - intron_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.-134_-132del - inframe_deletion De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.1049C>T p.Ala350Val missense_variant De novo NA - 29026562 Zipper R , et al. (2017)
c.2278G>A p.Gly760Ser missense_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.2312G>A p.Gly771Asp missense_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.2354C>T p.Pro785Leu missense_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.3277+5G>A - splice_site_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.3097C>T p.Gln1033Ter stop_gained De novo NA Simplex 25167861 Redin C , et al. (2014)
c.3576C>T p.Tyr1192= stop_gained De novo NA Simplex 30666632 Radley JA , et al. (2019)
c.2582+2T>C - splice_site_variant De novo NA Simplex 31415821 Barrie ES , et al. (2019)
c.1591C>T p.Arg531Trp stop_gained De novo NA Simplex 30666632 Radley JA , et al. (2019)
c.2272C>T p.Arg758Ter stop_gained De novo NA Simplex 31406558 Munnich A , et al. (2019)
c.3011T>C p.Leu1004Pro missense_variant De novo NA - 33368194 Lopergolo D et al. (2021)
c.3576C>T p.Tyr1192= stop_gained De novo NA Multiplex 30666632 Radley JA , et al. (2019)
c.999+8A>G - splice_region_variant Familial Maternal - 33368194 Lopergolo D et al. (2021)
c.3322C>T p.Gln1108Ter stop_gained De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.804del p.Tyr269ThrfsTer3 frameshift_variant De novo NA - 28815955 Helm BM , et al. (2017)
c.3433C>T p.Arg1145Ter stop_gained Unknown Not maternal - 30206421 Mignot C , et al. (2018)
c.2752G>T p.Val918Phe missense_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.804del p.Tyr269ThrfsTer3 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.2078del p.Gly693ValfsTer29 frameshift_variant Unknown - - 30206421 Mignot C , et al. (2018)
c.-94G>C - missense_variant Familial Maternal Multiplex 31906484 Ibarluzea N , et al. (2020)
c.3206G>C p.Arg1069Pro missense_variant Familial Maternal - 30206421 Mignot C , et al. (2018)
c.854del p.Pro285LeufsTer21 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.3065G>A p.Arg1022His missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.3415G>A p.Ala1139Thr missense_variant Unknown - Multiplex 30206421 Mignot C , et al. (2018)
c.2507C>T p.Ala836Val missense_variant De novo NA Simplex 30666632 Radley JA , et al. (2019)
c.51_61del p.Asn17LysfsTer62 frameshift_variant De novo NA - 25914188 Olson HE , et al. (2015)
c.738-1G>A - splice_site_variant Familial Maternal Multiplex 30206421 Mignot C , et al. (2018)
c.3412G>C p.Gly1138Arg missense_variant De novo NA Simplex 30666632 Radley JA , et al. (2019)
c.2582G>C p.Ser861Thr missense_variant De novo NA Simplex 24306141 Gandomi SK , et al. (2013)
c.2563C>T p.Arg855Ter stop_gained De novo NA Simplex 23674175 Tran Mau-Them F , et al. (2013)
c.3079del p.Leu1027SerfsTer75 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.4039dup p.Ala1347GlyfsTer40 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.1076_1078del p.Arg359del inframe_deletion Unknown - Simplex 31130284 Monies D , et al. (2019)
c.1885del p.His629MetfsTer4 frameshift_variant De novo NA - 33368194 Lopergolo D et al. (2021)
c.854del p.Pro285LeufsTer21 frameshift_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.3457del p.Arg1153GlyfsTer244 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.588_610del p.Arg197AlafsTer34 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
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.1405_1406del p.Lys469ValfsTer4 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.1744_1763del p.Arg582CysfsTer9 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.3817C>T p.Gln1273Ter stop_gained Familial Maternal Multiplex 31415821 Barrie ES , et al. (2019)
c.3613del p.Leu1205TrpfsTer192 frameshift_variant De novo NA - 33368194 Lopergolo D et al. (2021)
c.3780del p.Gln1261SerfsTer136 frameshift_variant De novo NA - 33368194 Lopergolo D et al. (2021)
c.1049C>A p.Pro350His missense_variant Familial Maternal Multiplex 26544041 Zhang Y , et al. (2015)
c.55_151delinsAT p.Ala19IlefsTer32 frameshift_variant De novo NA - 30206421 Mignot C , et al. (2018)
c.1170dup p.Gln391AlafsTer5 frameshift_variant De novo NA Simplex 32529990 Accogli A et al. (2020)
c.2117A>G p.Asn706Ser missense_variant Familial Maternal Simplex 30666632 Radley JA , et al. (2019)
c.804del p.Tyr269ThrfsTer3 frameshift_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.2278G>A p.Gly760Ser missense_variant De novo NA Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.2983C>T p.Arg995Trp missense_variant De novo NA Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.913del p.Leu305Ter frameshift_variant Unknown - Multi-generational 30763456 Zhou WZ , et al. (2019)
c.2052_2053del p.Cys684Ter frameshift_variant De novo NA Simplex 24306141 Gandomi SK , et al. (2013)
c.4110_4111del p.Tyr1371GlnfsTer15 frameshift_variant De novo NA - 33368194 Lopergolo D et al. (2021)
c.4419_4431del p.Ser1474ArgfsTer17 frameshift_variant De novo NA - 33368194 Lopergolo D et al. (2021)
c.4419del p.Ser1474ValfsTer21 frameshift_variant De novo NA Simplex 31415821 Barrie ES , et al. (2019)
c.1076G>A p.Arg359His missense_variant Familial Maternal Multiplex 33368194 Lopergolo D et al. (2021)
c.854del p.Pro285LeufsTer21 frameshift_variant De novo NA Simplex 33624935 Abe-Hatano C et al. (2021)
c.2529_2535del p.His843GlnfsTer62 frameshift_variant De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.4401del p.Gly1468AlafsTer27 frameshift_variant Unknown Not maternal - 30206421 Mignot C , et al. (2018)
c.104delinsGC p.Gln35ArgfsTer48 frameshift_variant De novo NA 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.849_850insG p.Pro284AlafsTer41 frameshift_variant De novo NA Multiplex 32530565 Suzuki T et al. (2020)
c.280C>T;c.895C>T p.Gln94Ter;p.Gln299Ter stop_gained De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.1240_1243del p.Asp414ArgfsTer54 frameshift_variant De novo NA 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.1567_2199delinsGGC p.Thr523_Thr733delinsGly inframe_deletion De novo NA - 30206421 Mignot C , et al. (2018)
c.770G>A p.Ser257Asn missense_variant Familial Maternal Extended multiplex 32529990 Accogli A et al. (2020)
c.626_627delinsT p.Ala209ValfsTer48 frameshift_variant De novo NA Simplex 30666632 Radley JA , et al. (2019)
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 NA Multiplex (monozygotic twins) 30666632 Radley JA , et al. (2019)
c.2203C>T p.Gln735Ter stop_gained De novo NA - 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

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%).

Score Delta: Score remained at 4S

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."

4/1/2021
4S
icon
4S

Score remained at 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%).

1/1/2021
4S
icon
4S

Score remained at 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%).

7/1/2020
4S
icon
4S

Score remained at 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%).

1/1/2020
4S
icon
4S

Score remained at 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%).

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
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%).

4/1/2019
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%).

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%).

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).

4/1/2018
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).

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).

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).

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).

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.
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
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).
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.
Submit New Gene

Report an Error