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


Susan M. Hiatt
Slavica Trajkova
Matteo Rossi Sebastiano
E Christopher Partridge
Fatima E. Abidi
Ashlyn Anderson
Muhammad Ansar
Stylianos E. Antonarakis
Azadeh Azadi
Ruxandra Bachmann-Gagescu
Andrea Bartuli
Caroline Benech
Jennifer L. Berkowitz
Michael J. Betti
Alfredo Brusco
Ashley Cannon
Giulia Caron
Yanmin Chen
Meagan E. Cochran
Tanner F. Coleman
Molly M. Crenshaw
Laurence Cuisset
Cynthia J. Curry
Hossein Darvish
Serwet Demirdas
Maria Descartes
Jessica Douglas
David A. Dyment
Houda Zghal Elloumi
Giuseppe Ermondi
Marie Faoucher
Emily G. Farrow, Children's Mercy HospitalFollow
Stephanie A. Felker
Heather Fisher
Anna C E Hurst
Pascal Joset
Melissa A. Kelly
Stanislav Kmoch
Benjamin R. Leadem
Michael J. Lyons
Marina Macchiaiolo
Martin Magner
Giorgia Mandrile
Francesca Mattioli
Megan McEown
Sarah K. Meadows
Livija Medne
Naomi J L Meeks
Sarah Montgomery
Melanie P. Napier
Marvin Natowicz
Kimberly M. Newberry
Marcello Niceta
Lenka Noskova
Catherine B. Nowak
Amanda G. Noyes
Matthew Osmond
Eloise J. Prijoles
Jada Pugh
Verdiana Pullano
Chloé Quélin
Simin Rahimi-Aliabadi
Anita Rauch
Sylvia Redon
Alexandre Reymond
Caitlin Schwager, Children's Mercy Kansas CityFollow
Elizabeth A. Sellars
Angela E. Scheuerle
Elena Shukarova-Angelovska
Cara Skraban
Elliot Stolerman
Bonnie Sullivan, Children's Mercy HospitalFollow
Marco Tartaglia
Isabelle Thiffault, Children's Mercy HospitalFollow
Kevin Uguen
Luis A. Umaña
Yolande van Bever
Saskia N. van der Crabben
Marjon A. van Slegtenhorst
Quinten Waisfisz
Camerun Washington
Lance H. Rodan
Richard M. Myers
Gregory M. Cooper

Document Type


Publication Date



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.

Journal Title

American journal of human genetics





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Last Page


MeSH Keywords

Humans; Male; Female; Neurodevelopmental Disorders; Intellectual Disability; Phenotype; Gene Expression Regulation; Face; Nervous System Malformations; Nuclear Proteins; Histone Demethylases


X-linked intellectual disability; ZMYM3; chromatin modifiers; neurodevelopmental disorder; transcriptional coregulators

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