Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features.
Publication/Presentation Date
9-4-2026
Abstract
ZNF536 encodes a C2H2 zinc-finger transcription factor that functions as a transcriptional repressor. While common noncoding variants at the ZNF536 locus have been reported to be associated with schizophrenia in a genome-wide association study (GWAS), the contribution of rare, protein-altering variants to human disease has not been systematically investigated. Through an international collaboration, we assembled a cohort of 21 affected individuals carrying 18 unique, rare, heterozygous, protein-altering ZNF536 variants. Most variants (15/18) were predicted loss-of-function (LoF) alleles, with the remainder being missense variants. Among families with available inheritance data (17/20), most variants arose de novo (12/17), while others were inherited from mosaic or mildly affected parents (5/17). Clinically, affected individuals presented with developmental delay along with high rates of autism spectrum disorder, intellectual disability, hyperactivity, aggressive behavior, anxiety, and hyperphagia; epilepsy and sleep disturbances were also frequently observed. To assess functional consequences of a proband-associated ZNF536 variant, we generated a Zfp536
ISSN
1537-6605
Published In/Presented At
Hiatt, S. M., Zhao, W., Wang, Z., Wan, Y., Chen, K., Wang, K., Tan, S., Barth, M., Bergant, G., Besnard, T., Boothe, E., Brunet, T., Bupp, C., Cogne, B., Cohen, J. S., Coubes, C., de Vries, B. B. A., Donald, M., Ellis, C. A., Riley Eriksson, S., … Guo, H. (2026). Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features. American journal of human genetics, S0002-9297(26)00314-9. Advance online publication. https://doi.org/10.1016/j.ajhg.2026.08.013
Disciplines
Medicine and Health Sciences | Pediatrics
PubMedID
42697193
Department(s)
Department of Pediatrics
Document Type
Article