Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features.
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Hiatt Susan M, Zhao Wenjing, Wang Zhongqing, Wan Yingjie, Chen Kewen, Wang Ke, Tan Senwei, Barth Magalie, Bergant Gaber, Besnard Thomas, Boothe Emily, Brunet Theresa, Bupp Caleb, Cogne Benjamin, Cohen Julie S, Coubes Christine, de Vries Bert B A, Donald Madison, Ellis Colin A, Riley Eriksson Stephanie, Ganne Benjamin, Genevieve David, Gerard Benedicte, Gonzalez Garcia Aixa, Hendon Laura G, Henig Noa, Huss Kristina, Isidor Bertrand, Laut Taylor, Leadem Benjamin R, Marco Elysa J, Marom Daphna, Mercimek-Andrews Saadet, Muir Alison M, Navet Benjamin, Ostojić Slavica, Peterlin Borut, Pfundt Rolph, Prentice Anna, Prouteau Clement, Robinette Bethany, Rots Dmitrijs, Taurina Gita, van Slegtenhorst Marjon, Volozonoka Ludmila, Wessels Marja, West Brayden, Zerem Ayelet, Zhang Yinhong, Zhu Baosheng, Ziegler Alban, Courdier Cécile, Fergelot Patricia, Van Gils Julien, Terek Shannon, VanNoy Grace E, Berlin Brianna, Buonomo Alexandra G, McKee Jillian L, Cooper Gregory M, Guo Hui
Аннотация
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 Zfp536p.Gln169Ter knock-in mouse model. Homozygous mutants were non-viable, while heterozygotes survived but displayed autism-like behaviors, increased anxiety, and impaired recognition memory. Embryonic brain analysis revealed reduced cortical size, cortical thickness, and decreased deep-layer neuronal density. These features are consistent with phenotypes of a publicly available mouse knockout model and support our clinical cohort findings that rare monoallelic LoF variants in ZNF536 underlie a genetic neurodevelopmental disorder characterized by developmental delay, autism, and behavioral dysregulation. The pathogenicity of missense variants in disease remains to be determined. These results support a role for ZNF536 as a dosage-sensitive regulator of cortical development.