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.

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References

Model Summary

The human de novo EBF3 variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model.

References