Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 100, Issue 1, Pages 138-150Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2016.11.020
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Funding
- National Jewish Health Flow Cytometry Core
- Action Medical Research
- Henry Smith Charity
- RP Fighting Blindness
- Fight for Sight
- Wendy Siegel Fund for Leukemia and Cancer Research
- Victor W. Bolie and Earleen D. Bolie Graduate Scholarship Fund
- Health Innovation Challenge Fund [HICF-1009-003]
- Wellcome Trust
- Department of Health
- Wellcome Trust Sanger Institute [WT098051]
- National Institute for Health Research through the Comprehensive Clinical Research Network
- Mining for Miracles
- British Columbia Children's Hospital Foundation
- Genome British Columbia
- Action Medical Research [2063] Funding Source: researchfish
- Medical Research Council [MR/N027302/1, MC_UP_1502/3, G1000848, MR/N025431/1] Funding Source: researchfish
- MRC [MR/N025431/1, MC_UP_1502/3, G1000848] Funding Source: UKRI
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Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation.
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