Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Novel de novo variant in 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 05;3(3):a001743 PMID: 28487885 PMCID: PMC5411688

Pubmed ID





Pathogenic variants in 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 (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 demonstrates strong support for the pathogenicity of p.(Arg163Trp). We show that our patient presents with phenotypes consistent with previously reported patients harboring 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 PN


Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Child, Preschool
DNA-Binding Proteins
Developmental Disabilities
Intellectual Disability
Language Development Disorders
Mutation, Missense
Neurodevelopmental Disorders
Transcription Factors
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad