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Cited by 21Genetics and Neurodevelopmental DisordersGenomics and Rare DiseasesGenomic variations and chromosomal abnormalities

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

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Hiatt, Susan M., Trajkova, Slavica, Sebastiano, Matteo Rossi, Partridge, E. Christopher, Abidi, Fatima E., Anderson, Ashlyn, Ansar, Muhammad, Antonarakis, Stylianos E. +76 more·2023·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2022.12.007PMC PMC9943726
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Abstract

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.

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Authors
Hiatt, S. M., Trajkova, S., Sebastiano, M. R., Partridge, E. C., Abidi, F. E., Anderson, A., Ansar, M., Antonarakis, S. E., Azadi, A., Bachmann-Gagescu, R., Bartuli, A., Benech, C., Berkowitz, J. L., Betti, M. J., Brusco, A., Cannon, A., Caron, G., Chen, Y., Cochran, M. E., Coleman, T. F., Crenshaw, M. M., Cuisset, L., Curry, C. J., Darvish, H., Demirdas, S., Descartes, M., Douglas, J., Dyment, D. A., Elloumi, H. Z., Ermondi, G., Faoucher, M., Farrow, E. G., Felker, S. A., Fisher, H., Hurst, A. C. E., Joset, P., Kelly, M. A., Kmoch, S., Leadem, B. R., Lyons, M. J., Macchiaiolo, M., Magner, M., Mandrile, G., Mattioli, F., McEown, M., Meadows, S. K., Medne, L., Meeks, N. J. L., Montgomery, S., Napier, M. P., Natowicz, M., Newberry, K. M., Niceta, M., Noskova, L., Nowak, C. B., Noyes, A. G., Osmond, M., Prijoles, E. J., Pugh, J., Pullano, V., Quélin, C., Rahimi-Aliabadi, S., Rauch, A., Redon, S., Reymond, A., Schwager, C. R., Sellars, E. A., Scheuerle, A. E., Shukarova-Angelovska, E., Skraban, C., Stolerman, E., Sullivan, B. R., Tartaglia, M., Thiffault, I., Uguen, K., Umaña, L. A., van Bever, Y., van der Crabben, S. N., van Slegtenhorst, M. A., Waisfisz, Q., Washington, C., Rodan, L. H., Myers, R. M., & Cooper, G. M.
Affiliations
  • HudsonAlpha Institute for Biotechnology (US)
  • University of Turin (IT)
  • Greenwood Genetic Center (US)
  • Dow University of Health Sciences (PK)
  • University of Geneva (CH)
  • Golestan University of Medical Sciences (IR)
  • Bambino Gesù Children's Hospital (IT)
  • Vanderbilt University Medical Center (US)
  • University of Alabama at Birmingham (US)
  • University of Colorado Anschutz (US)
  • Université Paris Cité (FR)
  • University of California, San Francisco (US)
  • Erasmus MC (NL)
  • Boston Children's Hospital (US)
  • Children's Hospital of Eastern Ontario (CA)
  • Centre National de la Recherche Scientifique (FR)
  • Children's Mercy Hospital (US)
  • Children's Medical Center (US)
  • University Hospital of Basel (CH)
  • Charles University (CZ)
  • Ospedale San Luigi Gonzaga (IT)
  • University of Lausanne (CH)
  • Cleveland Clinic (US)
  • University of Utah (US)
  • University of Zurich (CH)
  • Inserm (FR)
  • Arkansas Children's Hospital (US)
  • The University of Texas Southwestern Medical Center (US)
  • Children's Hospital of Philadelphia (US)
  • Amsterdam Neuroscience (NL)
Corresponding author
  • Hiatt, Susan M.
  • Cooper, Gregory M.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2023-02
Volume
110
Issue
2
Pages
215-227
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2022.12.007
PMC
PMC9943726
OpenAlex
W4313368991
Cited by
21
References
5
Citations by year
2026: 8 · 2025: 3 · 2024: 6 · 2023: 4
FWCI
1.96
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion)
  • IRIS (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • European Commission
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_182632, 320030_179547)
  • Ministero della Salute (RCR-2021-23671215)
  • University of Alabama at Birmingham
  • Children's Mercy Hospital
  • National Institute of Nursing Research (LX22NPO5107)
  • Fondazione CRT
  • Univerzita Karlova v Praze (UNCE/MED/007)
  • Ministerstvo Zdravotnictví Ceské Republiky (NV19-07-00136)
  • National Institute of Mental Health (F31MH126628)
  • Ministero dell’Istruzione, dell’Università e della Ricerca (FOE 2019, RVO VFN 64165)
  • National Human Genome Research Institute (UM1HG007301)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
neurodevelopmental disorders, neurodevelopmental delay, intellectual disability, X chromosome, transcriptional coregulators, chromatin modification, de novo mutations, maternally inherited variant, protein modeling, evolutionary constraints, facial gestalt
MeSH terms
Face, Female, Gene Expression Regulation, Humans, Male, Intellectual Disability, Nervous System Malformations, Nuclear Proteins, Phenotype, Histone Demethylases, Neurodevelopmental Disorders

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