Am J Hum Genet.: co-auth.: group Reymond

Am J Hum Genet. 2022 Dec 21;S0002-9297(22)00541-9. doi: 10.1016/j.ajhg.2022.12.007. Online ahead of print.

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Susan M Hiatt 1Slavica Trajkova 2Matteo Rossi Sebastiano 3E Christopher Partridge 4Fatima E Abidi 5Ashlyn Anderson 4Muhammad Ansar 6Stylianos E Antonarakis 7Azadeh Azadi 8Ruxandra Bachmann-Gagescu 9Andrea Bartuli 10Caroline Benech 11Jennifer L Berkowitz 12Michael J Betti 13Alfredo Brusco 2Ashley Cannon 14Giulia Caron 3Yanmin Chen 12Meagan E Cochran 4Tanner F Coleman 4Molly M Crenshaw 15Laurence Cuisset 16Cynthia J Curry 17Hossein Darvish 18Serwet Demirdas 19Maria Descartes 14Jessica Douglas 20David A Dyment 21Houda Zghal Elloumi 12Giuseppe Ermondi 3Marie Faoucher 22Emily G Farrow 23Stephanie A Felker 4Heather Fisher 24Anna C E Hurst 14Pascal Joset 25Melissa A Kelly 26Stanislav Kmoch 27Benjamin R Leadem 12Michael J Lyons 5Marina Macchiaiolo 10Martin Magner 28Giorgia Mandrile 29Francesca Mattioli 30Megan McEown 4Sarah K Meadows 4Livija Medne 31Naomi J L Meeks 32Sarah Montgomery 33Melanie P Napier 12Marvin Natowicz 34Kimberly M Newberry 4Marcello Niceta 10Lenka Noskova 27Catherine B Nowak 20Amanda G Noyes 12Matthew Osmond 21Eloise J Prijoles 5Jada Pugh 4Verdiana Pullano 2Chloé Quélin 35Simin Rahimi-Aliabadi 36Anita Rauch 37Sylvia Redon 38Alexandre Reymond 30Caitlin R Schwager 39Elizabeth A Sellars 40Angela E Scheuerle 41Elena Shukarova-Angelovska 42Cara Skraban 31Elliot Stolerman 5Bonnie R Sullivan 39Marco Tartaglia 10Isabelle Thiffault 23Kevin Uguen 38Luis A Umaña 41Yolande van Bever 19Saskia N van der Crabben 43Marjon A van Slegtenhorst 19Quinten Waisfisz 44Camerun Washington 5Lance H Rodan 45Richard M Myers 4Gregory M Cooper 46Affiliations expand


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.