De Novo Missense Variants in ZBTB47 Are Associated With Developmental Delays, Hypotonia, Seizures, Gait Abnormalities, and Variable Movement Abnormalities

Authors

Scott K Ward
Alexandrea Wadley
Chun-Hui Anne Tsai
Paul J Benke
Lisa Emrick
Kristen Fisher
Kimberly M Houck
Hongzheng Dai
Undiagnosed Diseases Network
Maria J Guillen Sacoto
William Craigen
Kimberly Glaser
David R Murdock
Luis Rohena
Karin E M Diderich
Hennie T Bruggenwirth
Brendan Lee
Carlos Bacino
Lindsay C Burrage
Jill A Rosenfeld

Publication Date

1-1-2024

Journal

American Journal of Medical Genetics Part A

DOI

10.1002/ajmg.a.63399

PMID

37743782

PMCID

PMC11221546

PubMedCentral® Posted Date

1-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Child, Humans, Autism Spectrum Disorder, Developmental Disabilities, Gait, Intellectual Disability, Movement Disorders, Muscle Hypotonia, Neurodevelopmental Disorders, Phenotype, Seizures, DNA-Binding Proteins, Transcription Factors, : ZBTB47, ZNF651, zinc finger, developmental delay, seizure, neurodevelopmental, movement disorder

Abstract

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.