EBF3

Gene Facts

• HGNC Symbol: EBF3 (HGNC:19087)
• HGNC Name: EBF transcription factor 3
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: COE3, DKFZp667B0210
• %HI: 3.89
• pLI: 1
• LOEUF: 0.35
• Cytoband: 10q26.3
• Genomic Coordinates:

  GRCh37/hg19:	chr10:131633497-131762538
  GRCh38/hg38:	chr10:129835233-129964274

• MANE Select Transcript: NM_001375380.1 ENST00000440978.2
• Function: Transcriptional activator (PubMed:28017373, PubMed:28017372, PubMed:28017370). Recognizes variations of the palindromic sequence 5'- ATTCCCNNGGGAATT-3' (By similarity). {ECO:0000250|UniProtKB:Q07802, ECO:0000269|PubMed:28017370, ECO:0000269|PubMed:28017372, ECO:0000269|PubMed:28017373}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-7257
• ClinGen Curation ID: CCID:007047
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 12/06/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• hypotonia, ataxia, and delayed development syndrome

HI Evidence

• PUBMED: 28017373
  Harms et al. identified siblings with a missense mutation p.R209W in the EBF3 gene inherited from a unaffected mother mosaic (17% leukocytes, 4% in buccal) for the variant. Authors used GeneMatcher and identified 8 additional unrelated patients with mutations within the EBF3 gene. Of the eight cases 4 were missese mutation (Pt4,6, 7, 8), two were nonsense mutations (Pt3 and Pt9), one splice site mutation (Pt5) and 1 was a 9bp duplication (Pt10). All eight were de novo in origin, predicted to effect protein, and were absent in 1000 genomes Browser, NHLBI Exome Sequencing Project Exome Variant Server and ExAC browser. Common features among all 10 individuals include intellectual disabillty, speech delay, ataxia and facial dysmorphism. Authors assessed whether EBF3 variants mediated transcription of the targeted gene CDKN1A reporter gene. The EBF3 had significantly reduced or no ability to activate transcription of reporter gene. In addition, the activation of the CDKN1A promoter was reduced by 40-50% when EBF3wt was co-expressed with the following mutations p.Gln305*, p.Arg303*,p.Asn66Asp, p.Tyr141Cys, and p.His157_Ile159dup, suggesting dominant-negative effect. Authors highlight the p.Gln305* nonsense variant is predicted to undergo nonsense mediated decay in vivo however the data suggests that the truncated protein p.Gln305* , if produced in vivo would only partially localized to the nucleus. According to the authors, it is unclear whether pathogenesis results from dominant-negative or loss of function. Nonsense variants are counted below as evidence for the HI score (see Deisseroth et al 2022).
• PUBMED: 28017370
  Sleven et al. 2017 describe 8 individuals from 7 unrelated families with variants within the EBF3 gene. The variants included three missense, two splice site, one frame shift and two nonsense variants. None of the variants were present in the ExAC browser. Five of the patients had de novo variants and 3 individuals (Pt1) and two siblings (Pt 7 and Pt8) showed low levels of alternative reads suggesting germ line mosaicism in the phenotypically unaffected parents. The mechanism for pathogenicity of the frameshift variant seen in Pt5 is suggested to be loss of function because it is predicted to undergo nonsense mediated decay. Authors stated that the nonsense variants seen in the siblings (Pt7 and Pt8) are likely to cause heterozygous loss of function . Authors also suggest that both splice variants (Pt3 and Pt6) are predicted to affect splicing and skipping of exon 3 and exon 6 resulting in frame shift and in-frame deletion, respectively, although formal testing was not done. The frameshift and nonsense variants are counted below as evidence for the HI score (see Deisseroth et al 2022).
• PUBMED: 35340043
  Deisseroth et al. 2022 (PMID 35340043) identified numerous frameshift and nonsense variants in the EBF3 gene in individuals with hypotonia, ataxia, and delayed development (HADD) syndrome. Additional features including facial dysmorphism, and brain, gastrointestinal and genitourinary anomalies were also present in multiple patients. Four de novo occurrences for these LOF (nonsense/frameshift with predicted NMD) variants were found in this study (table S1), and at least seven de novo LOF variants have been previously reported in the literature, according to the performed meta-analysis (table S2, PMIDs: 28017373, 28017370, 29162653, 32345733). Multiple missense and intronic/splicing variants as well as large deletions involving EBF3 are also reported in this publication but have not been evaluated at this time.
• PUBMED: 37090941
  Ciaccio et al 2023 (PMID 37090941) report 6 patients with phenotypes consistent with EBF3 related NDD/HADD syndrome. Identified variants are three de novo missense, a large deletion involving the gene (>6Mb) and a de novo frameshift (Patient 2, c.481delT (p.Cys161Alafs*21)) that has been counted as evidence for the HI score.

• HI Evidence Comments: EBF3 encodes a transcription factor that regulates gene expression via DNA methylation and chromatin modifications, and contributes to nervous system, immune system, bone, gastrointestinal tract, and muscle development (as reviewed by Deisseroth et al 2022, PMID 35340043). In 2017, several publications first reported EBF3 in relation to autosomal dominant hypotonia, ataxia, and delayed development (HADD) syndrome (Sleven et al., PMID: 28017370; Chao et al., PMID: 28017372; Harms et al., PMID: 28017373) (see https://search.clinicalgenome.org/kb/genes/HGNC:19087). While in early publications the mechanism of disease was still unclear, additional evidence is pointing to haploinsufficiency of EBF3 as one mechanism for associated EBF3-neurodevelopmental disorders and HADD syndrome. A total of at least 12 de novo ocurrences of frameshift/nonsense variants with predicted nonsense mediated decay have been reported in the literature (PMIDs: 28017373, 28017370, 29162653, 32345733, 35340043, 37090941) in individuals with phenotype consistent with HADD/EBF3-NDD. Large deletions involving EBF3 have been also reported but involve additional genes and have not been included here.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity

TS Published Evidence

• PUBMED: 34999443
  Ignatius et al. 2022 (PMID: 34999443) report eleven individuals from six families with EBF3 variants. One patient (P11) carries a mosaic de novo duplication/triplication of 888kb encompassing EBF3 and other genes (GLRX3, MGMT and C10orf143; genes not associated with disease at this time). Features in this patient include motor delay, hypotonia and asymmetric tone at four months; abnormal brain MRI, ataxia and tremor in chilhood, and dysmorphic features. No other pathogenic variants were identified by clinical trio exome analysis.

• TS Evidence Comments: No focal duplications of the EFB3 gene alone have been reported in the literature to our knowledge. The mosaic dup/trp reported by Ignatius et al. (2022) involving EBF3 seems relevant given the clinical features of the patient, however, there is an overlapping 0.9Mb duplication with similar gene content reported to be inherited from an unaffected parent in the Decipher database (https://www.deciphergenomics.org/patient/251288/genotype/24668/browser).