%0 Journal Article
%T ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder
%A Aline Kolmer
%A Alison M. Muir
%A Andrea M. Lewis
%A Ang¨¦lique Pichot
%A Anne Molitor
%A Anne-Marie Guerrot
%A Antoine Hanauer
%A Aurore Garde
%A Aurore Morlon
%A Bertrand Isidor
%A Bruno Kieffer
%A Carlos A. Bacino
%A Caroline Schluth-Bolard
%A Christel Thauvin-Robinet
%A Christina Y. Hung
%A Christopher T. Gordon
%A Cl¨¦mantine Dimartino
%A David H. Viskochil
%A David Hunt
%A Deciphering Developmental Disorders Study
%A Ekaterina L. Ivanova
%A Eva Erdmann
%A Fabien Dutreux
%A Fr¨¦d¨¦ric Tran Mau-Them
%A Gregory M. Cooper
%A G¨¦raldine Joly-Helas
%A Heather C. Mefford
%A Heather P. Crawford
%A Ingrid M. Wentzensen
%A Jamel Chelly
%A Jeanne Amiel
%A Jocelyn C¨¦raline
%A Kirsty McWalter
%A Laurence Faivre
%A Linyan Meng
%A Lydie Naegely
%A Magalie S. Leduc
%A Marl¨¨ne Rio
%A Mary K. Kukolich
%A Maya Chopra
%A Meredith Phillips
%A Mira Kharbanda
%A Nicod¨¨me Paul
%A Nina Gold
%A Nolwenn Jean-Mar£¿ais
%A No£¿l Mensah-Bonsu
%A Olaf Bodamer
%A Pinar Bayrak-Toydemir
%A Rafal Ploski
%A Raphael Carapito
%A Rhonda E. Schnur
%A Robert Smigiel
%A Sarah L. Dugan
%A Seema R. Lalani
%A Susan M. Hiatt
%A Tatiana Tvrdik
%A University of Washington Center for Mendelian Genomics
%A Victoria Harrison
%A Xia Wang
%A Zijie Sun
%J Archive of "American Journal of Human Genetics".
%D 2019
%R 10.1016/j.ajhg.2018.12.007
%X ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome
%K ZMIZ1
%K intellectual disability
%K neurodevelopmental disorder
%K neuronal positioning
%K transcriptional coactivation
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369415/