Prez Baca et al., 2024 described 42 individuals with protein-truncating variants or deletions of ZFHX3 exhibiting a syndromic form of intellectual disability characterized by global developmental delay, varying degrees of intellectual disability, behavioral problems (including nine individuals with autism spectrum disorder), hypotonia, recurrent facial features, postnatal growth retardation, and brachydactyly; ZFHX3 haploinsufficiency was found to associate with a specific methylation profile in whole blood extracted DNA. Furthermore, Prez Baca et al., 2024 observed that nuclear abundance of ZFHX3 increased during human brain development and neuronal differentiation and that ZFHX3 interacted with the chromatin remodeling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex and predominantly bound to promoters of genes involved in nervous system development. A number of de novo variants in ZFHX3, including a de novo frameshift variant, have also been identified in ASD probands from the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, and the MSSNG cohort, among others (De Rubeis et al., 2014; Iossifov et al., 2014; Hashimoto et al., 2016; Yuen et al., 2017; Lim et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022).
Molecular Function
This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. A heterozygous exonic trinucleotide repeat expansion (GGCn) in this gene has also been associated with spinocerebellar ataxia 4 (SCA4; OMIM 600223) (Wallenius et al., 2024).