Human Gene Module / Chromosome 10 / EBF3

EBF3early B-cell factor 3

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
10 / 25
Rare Variants / Common Variants
98 / 0
EAGLE Score
9.75
Moderate Learn More
Aliases
EBF3, COE3,  EBF-3,  HADDS,  O/E-2,  OE-2
Associated Syndromes
-
Chromosome Band
10q26.3
Associated Disorders
DD/NDD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Heterozygous mutations in the EBF3 gene are associated with hypotonia, ataxia, and delayed development syndrome (HADDS; OMIM 617330), a neurodevelopmental syndrome characterized by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia (Sleven et al., 2017; Chao et al., 2017; Harms et al., 2017; Blackburn et al., 2017); individuals in Chao et al., 2017 were reported as presenting with perseverative social behaviors and motor stereotypies. Tanaka et al., 2017 described seven novel individuals with de novo EBF3 mutations; two of these individuals presented with autism, two individuals presented with autistic features, and two individuals presented with delayed or absent social smile. A de novo missense variant in the EBF3 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; while this variant was novel (not present in dbSNP or ESP), it was predicted by PolyPhen-2 to be benign in Sanders et al., 2015. A de novo frameshift variant in the EBF3 gene was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020. Padhi et al., 2021 identified an excess of de novo variants in the enhancer hs737 in ASD probands [discovery (p =0.0172), replication (p = 2.5 103), and combined dataset (p = 1.1 104]; in vitro assessment of ASD-associated de novo variants in the hs737 enhancer demonstrated reduced enhancer activity in a neuronal cell line, and epigenomic analysis showed that hs737 was brain-specific and targeted the transcription factor gene EBF3 in human fetal brain. A phenotypic assessment of 41 individuals combined with a literature meta-analysis for a total of 83 individuals diagnosed with EBF3-related neurodevelopmental disorders in Deisseroth et al., 2022 found that autistic features were observed in 68% of the cohort, with a formal diagnosis of autism in 27% of the cohort; common autistic features included stereotypy (63%), poor eye contact (44%), noise aversion (53%) and an aversion to crowds (17%). Two de novo loss-of-function variants and four rare and potentially damaging missense variants in the EBF3 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; 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 this report identified EBF3 as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

This gene encodes a member of the early B-cell factor (EBF) family of DNA binding transcription factors. EBF proteins are involved in B-cell differentiation, bone development and neurogenesis, and may also function as tumor suppressors. The encoded protein inhibits cell survival through the regulation of genes involved in cell cycle arrest and apoptosis, and aberrant methylation or deletion of this gene may play a role in multiple malignancies including glioblastoma multiforme and gastric carcinoma.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to EBF3 (25 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 Support De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome Sleven H , et al. (2016) No -
3 Support A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3 Chao HT , et al. (2016) No -
4 Support Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism Harms FL , et al. (2016) No -
5 Support Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases Blackburn PR , et al. (2017) No -
6 Support Whole Gene Deletion of EBF3 Supporting Haploinsufficiency of This Gene as a Mechanism of Neurodevelopmental Disease Lopes F , et al. (2017) Yes DD, ID
7 Primary De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism Tanaka AJ , et al. (2017) No Autism or autistic features
8 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
9 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
10 Support - Hildebrand MS et al. (2020) No DD
11 Support - Rodin RE et al. (2021) Yes -
12 Recent Recommendation - Padhi EM et al. (2021) Yes Hypotonia, ataxia, and delayed development syndrom
13 Support - Mahjani B et al. (2021) Yes -
14 Support - Ignatius E et al. (2021) No -
15 Support - Woodbury-Smith M et al. (2022) Yes -
16 Recent Recommendation - Deisseroth CA et al. (2022) No ASD or autistic features, ADHD, epilepsy/seizures
17 Support - Kepler LD et al. (2022) No -
18 Recent Recommendation - Zhou X et al. (2022) Yes -
19 Support - Zhu J et al. (2023) No ID, Afs, stereotypy
20 Support - Spataro N et al. (2023) No -
21 Support - Ciaccio C et al. (2023) No -
22 Support - Sanchis-Juan A et al. (2023) No -
23 Support - Axel Schmidt et al. (2024) No -
24 Support - Liene Thys et al. (2024) No DD
25 Recent Recommendation - Ethan W Hollingsworth et al. (2025) Yes -
Rare Variants   (98)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 36937983 Zhu J et al. (2023)
- - copy_number_loss De novo - - 36937983 Zhu J et al. (2023)
- - copy_number_loss Unknown - - 36937983 Zhu J et al. (2023)
- - copy_number_loss De novo - - 37090941 Ciaccio C et al. (2023)
- - copy_number_gain De novo - - 34999443 Ignatius E et al. (2021)
- - copy_number_loss De novo - - 34999443 Ignatius E et al. (2021)
- - copy_number_loss Unknown - - 35340043 Deisseroth CA et al. (2022)
- - copy_number_loss De novo - Simplex 29062322 Lopes F , et al. (2017)
c.636+1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
A>G - intergenic_variant De novo - Simplex 34256850 Padhi EM et al. (2021)
G>A - intergenic_variant De novo - Simplex 34256850 Padhi EM et al. (2021)
T>C - intergenic_variant De novo - Simplex 34256850 Padhi EM et al. (2021)
- - copy_number_loss Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.907C>T p.Arg303Ter stop_gained De novo - - 28017373 Harms FL , et al. (2016)
c.913C>T p.Gln305Ter stop_gained De novo - - 28017373 Harms FL , et al. (2016)
c.1101+1G>T - splice_site_variant De novo - - 28017373 Harms FL , et al. (2016)
c.486-1G>A - splice_site_variant De novo - - 29162653 Tanaka AJ , et al. (2017)
c.454C>T p.Arg152Cys missense_variant Unknown - - 36937983 Zhu J et al. (2023)
c.164A>G p.Glu55Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.-19G>C - missense_variant De novo - Simplex 28017370 Sleven H , et al. (2016)
c.616C>T p.Arg206Ter stop_gained De novo - - 29162653 Tanaka AJ , et al. (2017)
c.422A>G p.Tyr141Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.482G>A p.Cys161Tyr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.49G>A p.Glu17Lys missense_variant De novo - - 33432195 Rodin RE et al. (2021)
c.86C>A p.Ser29Ter stop_gained De novo - - 35340043 Deisseroth CA et al. (2022)
c.1133T>A p.Val378Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.291+2del - splice_site_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.554+1G>C - splice_site_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.554+2T>G - splice_site_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.805A>G p.Ser269Gly missense_variant De novo - - 34256850 Padhi EM et al. (2021)
c.196A>G p.Asn66Asp missense_variant De novo - - 28017373 Harms FL , et al. (2016)
c.422A>G p.Tyr141Cys missense_variant De novo - - 28017373 Harms FL , et al. (2016)
c.512G>A p.Gly171Asp missense_variant De novo - - 28017373 Harms FL , et al. (2016)
c.530C>T p.Pro177Leu missense_variant De novo - - 28017373 Harms FL , et al. (2016)
c.485G>A p.Ser162Asn missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.422A>G p.Tyr141Cys missense_variant De novo - - 37090941 Ciaccio C et al. (2023)
c.512G>A p.Gly171Asp missense_variant De novo - - 37090941 Ciaccio C et al. (2023)
c.191A>C p.Lys64Thr missense_variant De novo - - 29162653 Tanaka AJ , et al. (2017)
c.292-6T>G - splice_region_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.232C>T p.Gln78Ter stop_gained De novo - Simplex 32094338 Husson T , et al. (2020)
c.355+1G>C - splice_site_variant De novo - Simplex 28017370 Sleven H , et al. (2016)
c.471C>A p.His157Gln missense_variant De novo - - 29162653 Tanaka AJ , et al. (2017)
c.626G>A p.Arg209Gln missense_variant De novo - - 29162653 Tanaka AJ , et al. (2017)
c.530C>T p.Pro177Leu missense_variant De novo - - 34999443 Ignatius E et al. (2021)
c.625C>T p.Arg209Trp missense_variant De novo - - 34999443 Ignatius E et al. (2021)
c.625C>T p.Arg209Trp missense_variant De novo - - 39213953 Liene Thys et al. (2024)
c.188G>A p.Arg63Gln missense_variant De novo - Simplex 36937983 Zhu J et al. (2023)
c.422A>G p.Tyr141Cys missense_variant De novo - Simplex 36937983 Zhu J et al. (2023)
c.487C>G p.Arg163Gly missense_variant De novo - Simplex 36937983 Zhu J et al. (2023)
c.631T>C p.Phe211Leu missense_variant De novo - Simplex 36937983 Zhu J et al. (2023)
c.-38_-37insCTTTCGGCC - inframe_insertion De novo - - 28017373 Harms FL , et al. (2016)
c.656T>C p.Val219Ala missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.-227_-224del - frameshift_variant De novo - Simplex 28017370 Sleven H , et al. (2016)
c.291+1G>A - splice_site_variant Familial - Multiplex 36980980 Spataro N et al. (2023)
c.487C>T p.Arg163Trp missense_variant De novo - - 28487885 Blackburn PR , et al. (2017)
c.386G>C p.Arg129Pro missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.422A>G p.Tyr141Cys missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.469C>T p.His157Tyr missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.471C>A p.His157Gln missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.482G>A p.Cys161Tyr missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.482G>T p.Cys161Phe missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.487C>T p.Arg163Trp missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.488G>A p.Arg163Gln missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.492C>G p.Cys164Trp missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.509G>A p.Cys170Tyr missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.625C>T p.Arg209Trp missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.626G>A p.Arg209Gln missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.486-2_486-1inv - splice_site_variant Unknown - - 35340043 Deisseroth CA et al. (2022)
c.1001T>G p.Phe334Cys missense_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.488G>A p.Arg163Gln missense_variant De novo - Simplex 28017372 Chao HT , et al. (2016)
c.488G>T p.Arg163Leu missense_variant De novo - Simplex 28017372 Chao HT , et al. (2016)
c.1183C>T p.His395Tyr stop_gained Familial Maternal - 34999443 Ignatius E et al. (2021)
c.872T>A p.Leu291Ter stop_gained De novo - Simplex 32345733 Hildebrand MS et al. (2020)
c.174G>A p.Pro58= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1222del p.Ile408SerfsTer27 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.530C>T p.Pro177Leu missense_variant De novo - Simplex 28017370 Sleven H , et al. (2016)
c.579G>T p.Lys193Asn missense_variant De novo - Simplex 28017370 Sleven H , et al. (2016)
c.49G>A p.Glu17Lys splice_site_variant De novo - Simplex 28017370 Sleven H , et al. (2016)
c.151_153delinsTGA p.Arg51Ter stop_gained De novo - - 35340043 Deisseroth CA et al. (2022)
c.481del p.Cys161AlafsTer21 frameshift_variant De novo - - 37090941 Ciaccio C et al. (2023)
c.244del p.Val82TrpfsTer50 frameshift_variant De novo - - 29162653 Tanaka AJ , et al. (2017)
c.1496G>C p.Gly499Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.292-6T>G - splice_region_variant Familial Maternal - 35340043 Deisseroth CA et al. (2022)
c.291del p.Glu98SerfsTer34 frameshift_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.305G>A p.Glu102Gly missense_variant Familial Paternal - 35340043 Deisseroth CA et al. (2022)
c.488G>C p.Arg163Pro missense_variant Familial Maternal - 35340043 Deisseroth CA et al. (2022)
c.481del p.Cys161AlafsTer21 frameshift_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.779del p.Ser260IlefsTer15 frameshift_variant De novo - - 35340043 Deisseroth CA et al. (2022)
c.1040G>A p.Gly347Asp missense_variant Familial Paternal - 35340043 Deisseroth CA et al. (2022)
c.840dup p.Asp281Ter frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1402_1414del p.Thr468ProfsTer10 frameshift_variant De novo - - 29162653 Tanaka AJ , et al. (2017)
c.625C>T p.Arg209Trp missense_variant Familial Maternal Multiplex 28017373 Harms FL , et al. (2016)
c.280_283del p.Glu94LysfsTer37 frameshift_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.616C>T p.Arg206Ter stop_gained De novo (germline mosaicism) - Multiplex 28017370 Sleven H , et al. (2016)
c.663_685del p.Asp222ArgfsTer34 frameshift_variant Familial Maternal Simplex 34256850 Padhi EM et al. (2021)
c.560_563del p.Phe187Ter frameshift_variant Familial Maternal Multiplex 35340043 Deisseroth CA et al. (2022)
c.1581_1582del p.Met528GlyfsTer12 frameshift_variant Familial - Extended multiplex 34256850 Padhi EM et al. (2021)
c.622dup p.Met208AsnfsTer56 frameshift_variant Familial Maternal Extended multiplex 34999443 Ignatius E et al. (2021)
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."

1/1/2021
1
icon
1

Score remained at 1

Description

Heterozygous mutations in the EBF3 gene are associated with hypotonia, ataxia, and delayed development syndrome (HADDS; OMIM 617330), a neurodevelopmental syndrome characterized by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia (Sleven et al., 2017; Chao et al., 2017; Harms et al., 2017; Blackburn et al., 2017); individuals in Chao et al., 2017 were reported as presenting with perseverative social behaviors and motor stereotypies. Tanaka et al., 2017 described seven novel individuals with de novo EBF3 mutations; two of these individuals presented with autism, two individuals presented with autistic features, and two individuals presented with delayed or absent social smile. A de novo missense variant in the EBF3 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; while this variant was novel (not present in dbSNP or ESP), it was predicted by PolyPhen-2 to be benign in Sanders et al., 2015.

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
1/1/2020
1
icon
1

Score remained at 1

Description

Heterozygous mutations in the EBF3 gene are associated with hypotonia, ataxia, and delayed development syndrome (HADDS; OMIM 617330), a neurodevelopmental syndrome characterized by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia (Sleven et al., 2017; Chao et al., 2017; Harms et al., 2017; Blackburn et al., 2017); individuals in Chao et al., 2017 were reported as presenting with perseverative social behaviors and motor stereotypies. Tanaka et al., 2017 described seven novel individuals with de novo EBF3 mutations; two of these individuals presented with autism, two individuals presented with autistic features, and two individuals presented with delayed or absent social smile. A de novo missense variant in the EBF3 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; while this variant was novel (not present in dbSNP or ESP), it was predicted by PolyPhen-2 to be benign in Sanders et al., 2015.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Heterozygous mutations in the EBF3 gene are associated with hypotonia, ataxia, and delayed development syndrome (HADDS; OMIM 617330), a neurodevelopmental syndrome characterized by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia (Sleven et al., 2017; Chao et al., 2017; Harms et al., 2017; Blackburn et al., 2017); individuals in Chao et al., 2017 were reported as presenting with perseverative social behaviors and motor stereotypies. Tanaka et al., 2017 described seven novel individuals with de novo EBF3 mutations; two of these individuals presented with autism, two individuals presented with autistic features, and two individuals presented with delayed or absent social smile. A de novo missense variant in the EBF3 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; while this variant was novel (not present in dbSNP or ESP), it was predicted by PolyPhen-2 to be benign in Sanders et al., 2015.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.53132184844142

Ranking 1539/25841 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 0.99859001376164

Ranking 1157/18225 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 0.94010716308957

Ranking 14448/18665 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 -0.35346458549528

Ranking 17858/20870 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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