Am J Hum Genet. 2023 Feb 2;110(2):215-227. doi: 10.1016/j.ajhg.2022.12.007. Epub 2022 Dec 30.
Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype
Susan M Hiatt 1, Slavica Trajkova 2, Matteo Rossi Sebastiano 3, E Christopher Partridge 4, Fatima E Abidi 5, Ashlyn Anderson 4, Muhammad Ansar 6, Stylianos E Antonarakis 7, Azadeh Azadi 8, Ruxandra Bachmann-Gagescu 9, Andrea Bartuli 10, Caroline Benech 11, Jennifer L Berkowitz 12, Michael J Betti 13, Alfredo Brusco 2, Ashley Cannon 14, Giulia Caron 3, Yanmin Chen 12, Meagan E Cochran 4, Tanner F Coleman 4, Molly M Crenshaw 15, Laurence Cuisset 16, Cynthia J Curry 17, Hossein Darvish 18, Serwet Demirdas 19, Maria Descartes 14, Jessica Douglas 20, David A Dyment 21, Houda Zghal Elloumi 12, Giuseppe Ermondi 3, Marie Faoucher 22, Emily G Farrow 23, Stephanie A Felker 4, Heather Fisher 24, Anna C E Hurst 14, Pascal Joset 25, Melissa A Kelly 26, Stanislav Kmoch 27, Benjamin R Leadem 12, Michael J Lyons 5, Marina Macchiaiolo 10, Martin Magner 28, Giorgia Mandrile 29, Francesca Mattioli 30, Megan McEown 4, Sarah K Meadows 4, Livija Medne 31, Naomi J L Meeks 32, Sarah Montgomery 33, Melanie P Napier 12, Marvin Natowicz 34, Kimberly M Newberry 4, Marcello Niceta 10, Lenka Noskova 27, Catherine B Nowak 20, Amanda G Noyes 12, Matthew Osmond 21, Eloise J Prijoles 5, Jada Pugh 4, Verdiana Pullano 2, Chloé Quélin 35, Simin Rahimi-Aliabadi 36, Anita Rauch 37, Sylvia Redon 38, Alexandre Reymond 30, Caitlin R Schwager 39, Elizabeth A Sellars 40, Angela E Scheuerle 41, Elena Shukarova-Angelovska 42, Cara Skraban 31, Elliot Stolerman 5, Bonnie R Sullivan 39, Marco Tartaglia 10, Isabelle Thiffault 23, Kevin Uguen 38, Luis A Umaña 41, Yolande van Bever 19, Saskia N van der Crabben 43, Marjon A van Slegtenhorst 19, Quinten Waisfisz 44, Camerun Washington 5, Lance H Rodan 45, Richard M Myers 4, Gregory M Cooper 46Affiliations expand
- PMID: 36586412
- DOI: 10.1016/j.ajhg.2022.12.007
Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.
Keywords: X-linked intellectual disability; ZMYM3; chromatin modifiers; neurodevelopmental disorder; transcriptional coregulators.