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

• Published in: American journal of human genetics Vol. 111; no. 3; pp. 509 - 528
• Main Authors: Pérez Baca, María del Rocío, Jacobs, Eva Z., Vantomme, Lies, Leblanc, Pontus, Bogaert, Elke, Dheedene, Annelies, De Cock, Laurenz, Haghshenas, Sadegheh, Foroutan, Aidin, Levy, Michael A., Kerkhof, Jennifer, McConkey, Haley, Chen, Chun-An, Batzir, Nurit Assia, Wang, Xia, Carels, Marieke, Agrawal, Pankaj, Armstrong Scott, Daryl, Bellini, Melissa, Beneteau, Claire, Bjørgo, Kathrine, Brooks, Alice, Brown, Natasha, Castle, Alison, Castro, Diana, Chorin, Odelia, Cleghorn, Mark, Clement, Emma, Coman, David, Costin, Carrie, Devriendt, Koen, Dong, Dexin, Dries, Annika, Duelund Hjortshøj, Tina, Dyment, David, Eng, Christine, Genetti, Casie, Grano, Siera, Henneman, Peter, Heron, Delphine, Hoffmann, Katrin, Du, Haowei, Isidor, Bertrand, Järvelä, Irma E., Jones, Julie, Keren, Boris, Kohlhase, Jürgen, Lalani, Seema, Le Caignec, Cedric, Lewis, Andi, Lovgren, Alysia, Lupski, James R., Lyons, Mike, Lysy, Philippe, Manning, Melanie, Marcelis, Carlo, McLean, Scott Douglas, Mercie, Sandra, Mertens, Mareike, Molin, Arnaud, Nugent, Kimberly Margaret, Öhman, Susanna, O'Leary, Melanie, Okashah Littlejohn, Rebecca, Petit, Florence, Pfundt, Rolph, Pottocki, Lorraine, Raas-Rotschild, Annick, Ranguin, Kara, Revencu, Nicole, Rosenfeld, Jill, Rhodes, Lindsay, Sals, Karen, Schrauwen, Isabelle, Schuurs-Hoeijmakers, Janneke H.M., Seaby, Eleanor G., Sheffer, Ruth, Snijders Blok, Lot, Sørensen, Kristina P., Srivastava, Siddharth, Stark, Zornitza, Stoeva, Radka, Stutterd, Chloe, Tan, Natalie B., Mathiesen Torring, Pernille, Vanakker, Olivier, van der Laan, Liselot, Ververi, Athina, Vincent, Marie, Wand, Dorothea, Wessels, Marja, White, Sue, Wojcik, Monica H., Wu, Nan, Zhao, Sen, Dermaut, Bart, Sadikovic, Bekim, Yuan, Bo, Vergult, Sarah, Callewaert, Bert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2024
• Subjects: Autism Spectrum Disorder; Brain - metabolism; chromatin remodeling complex; Haploinsufficiency - genetics; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Intellectual Disability - complications; Intellectual Disability - genetics; mRNA polyadenylation and cleavage complex; neurodevelopmental disorder; Neurodevelopmental Disorders - genetics; ZFHX3; mRNA polyadenylation and cleavage complex; ZFHX3; neurodevelopmental disorder; chromatin remodeling complex
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2024.01.013

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. [Display omitted] We identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability. We show that LoF is associated with a specific methylation signature and that ZFHX3 targets promoters of genes implicated in neural development. Proteomics analysis indicates a contribution of ZFHX3 to chromatin remodeling and pre-messenger RNA processing.