Publication Date
3-7-2024
Journal
The American Journal of Human Genetics
DOI
10.1016/j.ajhg.2024.01.013
PMID
38412861
PMCID
PMC10940049
PubMedCentral® Posted Date
2-26-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Humans, Intellectual Disability, Autism Spectrum Disorder, Haploinsufficiency, Neurodevelopmental Disorders, Brain, Homeodomain Proteins
Abstract
Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability (ID). ZFHX3 is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tumorigenesis. We describe 42 individuals with protein-truncating variants (PTVs) or (partial) deletions of ZFHX3, exhibiting variable intellectual disability and autism spectrum disorder, recurrent facial features, relative short stature, brachydactyly, and, rarely, cleft palate. ZFHX3 LoF associates with a specific methylation profile in whole blood extracted DNA. Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation. ZFHX3 was found to interact with the chromatin remodeling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex, suggesting a function in chromatin remodeling and mRNA processing. Furthermore, ChIP-seq for ZFHX3 revealed that it predominantly binds promoters of genes involved in nervous system development. We conclude that loss-of-function variants in ZFHX3 are a cause of syndromic ID associating with a specific DNA methylation profile.
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