Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability

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.