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De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome.

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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Sleven H,Welsh SJ,Yu J,Churchill MEA,Wright CF,Henderson A,Horvath R,Rankin J,Vogt J,Magee A,McConnell V,Green A,King MD,Cox H,Armstrong L,Lehman A,Nelson TN,Deciphering Developmental Disorders study.,CAUSES study.,

doi

10.1016/j.ajhg.2016.11.020

subject

Has Abstract

pub_date

2017-01-05 00:00:00

pages

138-150

issue

1

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(16)30524-9

journal_volume

100

pub_type

杂志文章

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