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

2024; Elsevier BV; Volume: 111; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2024.01.013

1537-6605

María del Rocío Pérez Baca, Eva Jacobs, Lies Vantomme, Pontus Leblanc, Elke Bogaert, Annelies Dheedene, Laurenz De Cock, Sadegheh Haghshenas, Aidin Foroutan, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Chun‐An Chen, Nurit Assia Batzir, Xia Wang, María Palomares‐Bralo, Marieke Carels, Pankaj B. Agrawal, Daryl A. Scott, Elizabeth Barkoudah, Melissa Bellini, Claire Bénéteau, Kathrine Bjørgo, Alice S. Brooks, Natasha J. Brown, Alison M. R. Castle, Diana Castro, Odelia Chorin, Mark Cleghorn, Emma Clement, David Coman, Carrie Costin, Koenraad Devriendt, Daixing Dong, Annika M. Dries, Tina Duelund Hjortshøj, David A. Dyment, Christine M. Eng, Casie A. Genetti, Siera Grano, Peter Henneman, Delphine Héron, Katrin Hoffmann, Jason Hom, Haowei Du, Maria Iascone, Bertrand Isidor, Irma Järvelä, Julie R. Jones, Boris Keren, Mary Kay Koenig, Jürgen Kohlhase, Seema R. Lalani, Cédric Le Caignec, Andrew Lewis, Pengfei Liu, Alysia Kern Lovgren, James R. Lupski, Mike Lyons, Philippe A. Lysy, Melanie Manning, Carlo Marcelis, Scott McLean, Sandra Mercie, Mareike Mertens, Arnaud Molin, Mathilde Nizon, Kimberly Nugent, Susanna Öhman, Melanie O’Leary, Rebecca O. Littlejohn, Florence Petit, Rolph Pfundt, Lorraine Pottocki, Annick Raas‐Rotschild, Kara Ranguin, Nicole Revençu, Jill A. Rosenfeld, Lindsay Rhodes, Fernando Santos Simmaro, Karen Sals, Jolanda Schieving, Isabelle Schrauwen, Janneke Schuurs-Hoeijmakers, Eleanor G. Seaby, Ruth Sheffer, Lot Snijders Blok, Kristina P. Sørensen, Siddharth Srivastava, Zornitza Stark, Radka Stoeva, Chloe Stutterd, Natalie B. Tan, Pernille Mathiesen Tørring, Olivier Vanakker, Liselot van der Laan, Athina Ververi, Pablo Villavicencio‐Lorini, Marie Vincent, Dorothea Wand, Marja W. Wessels, S. White, Monica H. Wojcik, Nan Wu, Sen Zhao, Bart Dermaut, Bekim Sadiković, Björn Menten, Bo Yuan, Sarah Vergult, Bert Callewaert,

Genomics and Rare Diseases

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.