Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases. Cold Spring Harb Mol Case Stud 2017 May;3(3):a001743
Date
05/11/2017Pubmed ID
28487885Pubmed Central ID
PMC5411688DOI
10.1101/mcs.a001743Abstract
Pathogenic variants in EBF3 were recently described in three back-to-back publications in association with a novel neurodevelopmental disorder characterized by intellectual disability, speech delay, ataxia, and facial dysmorphisms. In this report, we describe an additional patient carrying a de novo missense variant in EBF3 (c.487C>T, p.(Arg163Trp)) that falls within a conserved residue in the zinc knuckle motif of the DNA binding domain. Without a solved structure of the DNA binding domain, we generated a homology-based atomic model and performed molecular dynamics simulations for EBF3, which predicted decreased DNA affinity for p.(Arg163Trp) compared with wild-type protein and control variants. These data are in agreement with previous experimental studies of EBF1 showing the paralogous residue is essential for DNA binding. The conservation and experimental evidence existing for EBF1 and in silico modeling and dynamics simulations to validate comparable behavior of multiple variants in EBF3 demonstrates strong support for the pathogenicity of p.(Arg163Trp). We show that our patient presents with phenotypes consistent with previously reported patients harboring EBF3 variants and expands the phenotypic spectrum of this newly identified disorder with the additional feature of a bicornuate uterus.
Author List
Blackburn PR, Barnett SS, Zimmermann MT, Cousin MA, Kaiwar C, Pinto E Vairo F, Niu Z, Ferber MJ, Urrutia RA, Selcen D, Klee EW, Pichurin PNAuthors
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of WisconsinMichael T. Zimmermann PhD Director, Assistant Professor in the Data Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Child, PreschoolDNA
DNA-Binding Proteins
Developmental Disabilities
Exome
Female
Humans
Intellectual Disability
Language Development Disorders
Mutation
Mutation, Missense
Neurodevelopmental Disorders
Phenotype
Transcription Factors
