EBF3early B-cell factor 3

SFARI Gene Score

High Confidence, Syndromic Criteria 1.1, Syndromic

Autism Reports / Total Reports

9 / 23

Rare Variants / Common Variants

97 / 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.

SFARI Genomic Platforms

GPF browser SFARI genome browser

Reports (23)
Variants (97)
Gene Score

Reports related to EBF3 (23 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	-

Rare Variants (97)

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.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.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.174G>A	p.Pro58%3D	synonymous_variant	Unknown	-	-	35205252	Woodbury-Smith M 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.

Current Score
Scoring History
3rd Party Scoring

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

See SFARI Gene'scoring criteria

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.

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

Score remained at 1

Description

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

Score remained at 1

Description

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

Increased from S to 1

New Scoring Scheme

Description

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

Human Gene Module / Chromosome 10 / EBF3

EBF3early B-cell factor 3

SFARI Gene Score

Autism Reports / Total Reports

Rare Variants / Common Variants

EAGLE Score

Aliases

Associated Syndromes

Chromosome Band

Associated Disorders

Genetic Category

Relevance to Autism

Molecular Function

External Links

Human

Fruit fly

SFARI Genomic Platforms

Reports related to EBF3 (23 Reports)

Rare Variants (97)

Common Variants

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

High Confidence

Syndromic

1/1/2021

Score remained at 1

Description

Reports Added

1/1/2020

Score remained at 1

Description

Reports Added

10/1/2019

Increased from S to 1

New Scoring Scheme

Description

Reports Added

Krishnan Probability Score

Score 0.53132184844142

Ranking 1539/25841 scored genes

ExAC Score

Score 0.99859001376164

Ranking 1157/18225 scored genes

Sanders TADA Score

Score 0.94010716308957

Ranking 14448/18665 scored genes

Zhang D Score

Score -0.35346458549528

Ranking 17858/20870 scored genes