De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome

Am J Hum Genet. 2017 Jan 5;100(1):138-150. doi: 10.1016/j.ajhg.2016.11.020.

Hannah Sleven ¹, Seth J Welsh ², Jing Yu ¹, Mair E A Churchill ³, Caroline F Wright ⁴, Alex Henderson ⁵, Rita Horvath ⁶, Julia Rankin ⁷, Julie Vogt ⁸, Alex Magee ⁹, Vivienne McConnell ⁹, Andrew Green ¹⁰, Mary D King ¹¹, Helen Cox ⁸, Linlea Armstrong ¹², Anna Lehman ¹², Tanya N Nelson ¹³, Deciphering Developmental Disorders study ⁴, CAUSES study ¹², Jonathan Williams ¹⁴, Penny Clouston ¹⁴, James Hagman ¹⁵, Andrea H Németh ¹⁶

Affiliations

1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
2 Program in Molecular Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
3 Program in Molecular Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
5 Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
6 John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
7 Peninsula Clinical Genetics Service, Exeter EX1 2ED, UK.
8 West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
9 Department of Genetic Medicine, Belfast City Hospital, Belfast BT9 7AB, UK.
10 Department of Clinical Genetics, Our Lady's Hospital, Crumlin, Dublin D12 N512, Ireland; Health Science Centre, School of Medicine & Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
11 Department of Paediatric Neurology and Clinical Neurophysiology, Temple Street Children's University Hospital, Dublin 1, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
12 Department of Medical Genetics, Children's & Women's Health Centre of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
13 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Pathology and Laboratory Medicine, BC Children's and BC Women's Hospitals, Vancouver, BC V6H 3N1, Canada.
14 Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LJ, UK.
15 Program in Molecular Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. Electronic address: [email protected].
16 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK; Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Windmill Road, Headington, Oxford OX3 7HE, UK. Electronic address: [email protected].

PMID: 28017370 DOI: 10.1016/j.ajhg.2016.11.020

Abstract

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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