Human Gene Module / Chromosome 14 / IRF2BPL

IRF2BPLInterferon regulatory factor 2 binding protein-like

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
11 / 17
Rare Variants / Common Variants
37 / 0
EAGLE Score
9
Moderate Learn More
Aliases
IRF2BPL, C14orf4,  EAP1
Associated Syndromes
-
Chromosome Band
14q24.3
Associated Disorders
EP, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

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). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Marcogliese et al., 2018 reported seven individuals with damaging heterozygous variants in the IRF2BPL gene; the most commonly observed phenotypes in these individuals included developmental regression, hypotonia, and seizures, and one individual was also diagnosed with ASD. Mau-Them et al., 2018 identified 11 unrelated individuals with developmental epileptic encephalopathy and de novo truncating variants in the IRF2BPL gene; one of the individuals reported in this study (patient 9) also presented with autism. A de novo likely gene-disruptive variant in IRF2BPL was identified in an ASD proband from the SPARK cohort in Feliciano et al, 2019; a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA in this report identified IRF2BPL as an ASD candidate gene with a false discovery rate between 0.01 and 0.05 (0.01 < FDR 0.05). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified IRF2BPL as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

This gene encodes a transcription factor that may play a role in regulating female reproductive function. It may play a role in gene transcription by transactivating the GNRH1 promoter and repressing the PENK promoter.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to IRF2BPL (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
3 Primary Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
4 Recent Recommendation IRF2BPL Is Associated with Neurological Phenotypes Marcogliese PC , et al. (2018) No -
5 Recent Recommendation De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy Tran Mau-Them F , et al. (2018) No ASD
6 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Support - Taşkıran EZ et al. (2021) No Epilepsy/seizures, autistic features
9 Support - Woodbury-Smith M et al. (2022) Yes -
10 Support - Marcogliese PC et al. (2022) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Miyake N et al. (2023) Yes -
13 Support - Horovitz DDG et al. (2023) No Epilepsy/seizures
14 Support - Kipkemoi P et al. (2023) No -
15 Support - Solveig Heide et al. (2023) No DD, cerebellar ataxia
16 Support - Marketa Wayhelova et al. (2024) Yes -
17 Support - Ruohao Wu et al. (2024) Yes -
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1133C>G p.Thr378Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.376C>T p.Gln126Ter stop_gained De novo - - 30057031 Marcogliese PC , et al. (2018)
c.379C>T p.Gln127Ter stop_gained Unknown - - 30057031 Marcogliese PC , et al. (2018)
c.514C>T p.Glu172Ter stop_gained De novo - - 30057031 Marcogliese PC , et al. (2018)
c.562C>T p.Arg188Ter stop_gained De novo - - 30057031 Marcogliese PC , et al. (2018)
c.562C>T p.Arg188Ter stop_gained Unknown - - 30057031 Marcogliese PC , et al. (2018)
c.361C>T p.Gln121Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.376C>T p.Gln126Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.496G>T p.Glu166Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.519C>G p.Tyr173Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.562C>T p.Arg188Ter stop_gained De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.90C>G p.Phe30Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1099G>T p.Glu367Ter stop_gained De novo - Simplex 37346291 Horovitz DDG et al. (2023)
c.1133C>G p.Thr378Arg missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1115C>G p.Pro372Arg missense_variant De novo - - 30057031 Marcogliese PC , et al. (2018)
c.1254G>C p.Lys418Asn missense_variant De novo - - 30057031 Marcogliese PC , et al. (2018)
c.474_491del p.Ala159_Ala164del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.1230G>T p.Lys410Asn missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
- p.Cys714AlafsTer49 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.2175G>C p.Thr725%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2136_2137dup p.Leu713ProfsTer55 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1794del p.Pro599ArgfsTer81 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.938C>A p.Ser313Ter stop_gained Familial Maternal Simplex 38235039 Solveig Heide et al. (2023)
c.962del p.Ala321GlufsTer24 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.508del p.Arg170AlafsTer9 frameshift_variant De novo - - 38321498 Marketa Wayhelova et al. (2024)
c.2122del p.Ala708ProfsTer59 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.2152del p.Cys718AlafsTer49 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.2102del p.Asn701ThrfsTer66 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2137del p.Leu713SerfsTer54 frameshift_variant De novo - Simplex 37463579 Kipkemoi P et al. (2023)
c.349C>T p.Gln117Ter stop_gained Familial - Multi-generational 38235039 Solveig Heide et al. (2023)
c.590del p.Asn197ThrfsTer15 frameshift_variant Unknown - Simplex 37346291 Horovitz DDG et al. (2023)
c.2102del p.Asn701ThrfsTer66 frameshift_variant De novo - Simplex 37346291 Horovitz DDG et al. (2023)
c.474_504del p.Ala161SerfsTer8 frameshift_variant Unknown - Simplex 37346291 Horovitz DDG et al. (2023)
c.2136_2137del p.Cys714LeufsTer30 frameshift_variant De novo - - 30166628 Tran Mau-Them F , et al. (2018)
c.220_221delinsA p.Pro74SerfsTer78 frameshift_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.527del p.Pro176ArgfsTer3 frameshift_variant De novo - Simplex 33739554 Taşkıran EZ et al. (2021)
c.1484_1486delinsCGT p.Leu495_Pro496delinsProSer inframe_indel De novo (germline mosaicism) - Multiplex 36973392 Miyake N et al. (2023)
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
icon
1

Score remained at 1

Description

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). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Marcogliese et al., 2018 reported seven individuals with damaging heterozygous variants in the IRF2BPL gene; the most commonly observed phenotypes in these individuals included developmental regression, hypotonia, and seizures, and one individual was also diagnosed with ASD. Mau-Them et al., 2018 identified 11 unrelated individuals with developmental epileptic encephalopathy and de novo truncating variants in the IRF2BPL gene; one of the individuals reported in this study (patient 9) also presented with autism.

Reports Added
[Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability2021]
1/1/2020
1
icon
1

Score remained at 1

Description

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). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Marcogliese et al., 2018 reported seven individuals with damaging heterozygous variants in the IRF2BPL gene; the most commonly observed phenotypes in these individuals included developmental regression, hypotonia, and seizures, and one individual was also diagnosed with ASD. Mau-Them et al., 2018 identified 11 unrelated individuals with developmental epileptic encephalopathy and de novo truncating variants in the IRF2BPL gene; one of the individuals reported in this study (patient 9) also presented with autism.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

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). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Marcogliese et al., 2018 reported seven individuals with damaging heterozygous variants in the IRF2BPL gene; the most commonly observed phenotypes in these individuals included developmental regression, hypotonia, and seizures, and one individual was also diagnosed with ASD. Mau-Them et al., 2018 identified 11 unrelated individuals with developmental epileptic encephalopathy and de novo truncating variants in the IRF2BPL gene; one of the individuals reported in this study (patient 9) also presented with autism.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2018
2
icon
2S

Decreased from 2 to 2S

Description

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). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Marcogliese et al., 2018 reported seven individuals with damaging heterozygous variants in the IRF2BPL gene; the most commonly observed phenotypes in these individuals included developmental regression, hypotonia, and seizures, and one individual was also diagnosed with ASD. Mau-Them et al., 2018 identified 11 unrelated individuals with developmental epileptic encephalopathy and de novo truncating variants in the IRF2BPL gene; one of the individuals reported in this study (patient 9) also presented with autism.

Reports Added
[IRF2BPL Is Associated with Neurological Phenotypes.2018] [De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.2018]
10/1/2015
icon
2

Increased from to 2

Description

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). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Krishnan Probability Score

Score 0.49631658011089

Ranking 2624/25841 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 0.9689353461122

Ranking 2385/18225 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
Iossifov Probability Score

Score 0.958

Ranking 74/239 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
Original Source
Sanders TADA Score

Score 0.086375716290276

Ranking 60/18665 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 0.14060358626709

Ranking 5348/20870 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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