De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome

被引：48

作者：

Sleven, Hannah ^{[1
]}

Welsh, Seth J. ^{[2
]}

Yu, Jing ^{[1
]}

Churchill, Mair E. A. ^{[2
,3
]}

Wright, Caroline F. ^{[4
]}

Henderson, Alex ^{[5
]}

Horvath, Rita ^{[6
]}

Rankin, Julia ^{[7
]}

Vogt, Julie ^{[8
]}

Magee, Alex ^{[9
]}

McConnell, Vivienne ^{[9
]}

Green, Andrew ^{[10
,11
]}

King, Mary D. ^{[12
,13
]}

Cox, Helen ^{[8
]}

Armstrong, Linlea ^{[14
]}

Lehman, Anna ^{[14
]}

Nelson, Tanya N. ^{[15
,16
,17
]}

Williams, Jonathan ^{[18
]}

Clouston, Penny ^{[18
]}

Hagman, James ^{[2
,19
]}

Nemeth, Andrea H. ^{[1
,20
]}

机构：

[1] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

[2] Univ Colorado, Program Mol Biol, Anschutz Med Campus, Aurora, CO 80045 USA

[3] Univ Colorado, Dept Pharmacol, Anschutz Med Campus, Aurora, CO 80045 USA

[4] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SA, England

[5] Newcastle Upon Tyne Hosp NHS Fdn Trust, Northern Genet Serv, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[6] Newcastle Univ, Inst Med Genet, John Walton Muscular Dystrophy Res Ctr, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[7] Peninsula Clin Genet Serv, Exeter EX1 2ED, Devon, England

[8] Birmingham Womens Hosp, Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England

[9] Belfast City Hosp, Dept Med Genet, Belfast BT9 7AB, Antrim, North Ireland

[10] Our Ladys Hosp Sick Children, Dept Clin Genet, Dublin D12 N512, Ireland

[11] Univ Coll Dublin, Sch Med & Med Sci, Hlth Sci Ctr, Dublin 4, Ireland

[12] Temple St Childrens Univ Hosp, Dept Paediat Neurol & Clin Neurophysiol, Dublin 1, Ireland

[13] Univ Coll Dublin, Sch Med & Med Sci, Acad Ctr Rare Dis, Dublin 4, Ireland

[14] Childrens & Womens Hlth Ctr British Columbia, Dept Med Genet, 4500 Oak St, Vancouver, BC V6H 3N1, Canada

[15] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada

[16] BC Childrens Hosp, Dept Pathol & Lab Med, Vancouver, BC V6H 3N1, Canada

[17] BC Womens Hosp, Dept Pathol & Lab Med, Vancouver, BC V6H 3N1, Canada

[18] Oxford Univ Hosp NHS Fdn Trust, Churchill Hosp, Oxford Med Genet Labs, Oxford OX3 7LJ, England

[19] Natl Jewish Hlth, Dept Biomed Res, Denver, CO 80206 USA

[20] Oxford Univ Hosp NHS Fdn Trust, Nuffield Orthopaed Ctr, Oxford Ctr Genom Med, Windmill Rd, Oxford OX3 7HE, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2017年 / 100卷 / 01期

基金：

英国惠康基金;

关键词：

B-CELL FACTOR; TRANSCRIPTION FACTOR; NEURONAL DIFFERENTIATION; GENES; FRAMEWORK; FAMILY; SPECIFICATION; RECOGNITION; ACTIVATION; REGULATOR;

D O I：

10.1016/j.ajhg.2016.11.020

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：138 / 150

页数：13

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