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Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype
SM. Hiatt, S. Trajkova, MR. Sebastiano, EC. Partridge, FE. Abidi, A. Anderson, M. Ansar, SE. Antonarakis, A. Azadi, R. Bachmann-Gagescu, A. Bartuli, C. Benech, JL. Berkowitz, MJ. Betti, A. Brusco, A. Cannon, G. Caron, Y. Chen, ME. Cochran, TF....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
UM1 HG007301
NHGRI NIH HHS - United States
NLK
Cell Press Free Archives
from 1997-01-01 to 6 months ago
Free Medical Journals
from 1949 to 6 months ago
PubMed Central
from 1949 to 6 months ago
Europe PubMed Central
from 1949 to 6 months ago
Open Access Digital Library
from 2005-01-01
- MeSH
- Phenotype MeSH
- Histone Demethylases genetics MeSH
- Nuclear Proteins genetics MeSH
- Humans MeSH
- Nervous System Malformations * MeSH
- Intellectual Disability * genetics MeSH
- Neurodevelopmental Disorders * genetics MeSH
- Face MeSH
- Gene Expression Regulation MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Amsterdam Neuroscience Amsterdam The Netherlands
Amsterdam University Medical Centers Department of Clinical Genetics Amsterdam the Netherlands
Boston Children's Hospital Boston MA USA
Center for Integrative Genomics University of Lausanne Lausanne Switzerland
Centre de Référence Déficiences Intellectuelles de causes rares Brest France
Children's Hospital of Eastern Ontario Research Institute Ottawa ON Canada
Children's Medical Center Dallas TX USA
Children's Mercy Kansas City Center for Pediatric Genomic Medicine Kansas City KS USA
Childrens Hospital of Philadelphia Philadelphia PA USA
Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam the Netherlands
Department of Genetic Medicine and Development University of Geneva Geneva Switzerland
Department of Genetics University of Alabama at Birmingham Birmingham AL USA
Department of Medical Sciences University of Torino 10126 Torino Italy
Division of Genetics and Metabolism Children's Health Dallas TX USA
Division of Genetics Children's Mercy Kansas City Kansas City MO USA
GeneDx LLC Gaithersburg MD 20877 USA
Genetic Medicine UCSF Fresno Fresno CA 93701 USA
Genetics and Metabolism Arkansas Children's Hospital Little Rock AR 72202 USA
Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Gesù IRCCS 00146 Rome Italy
Greenwood Genetic Center Greenwood SC 29646 USA
Harvard Medical School Boston MA 02115 USA
HudsonAlpha Clinical Services Lab LLC Huntsville AL 35806 USA
HudsonAlpha Institute for Biotechnology Huntsville AL 35806 USA
Institute of Medical Genetics University of Zurich Schlieren 8952 Switzerland
Neuroscience Research Center Faculty of Medicine Golestan University of Medical Sciences Gorgan Iran
Nikagene Genetic Diagnostic Laboratory Gorgan Golestan Iran
Obestetrics and Gynecology Department Golestan University of Medical Sciences Gorgan Iran
Pediatrics and Medical Genetics University of Colorado Aurora CO USA
Service de Génétique Médicale et Biologie de la Reproduction CHU de Brest Brest France
Service de Génétique Moléculaire et Génomique CHU Rennes 35033 France
Univ Brest Inserm EFS UMR 1078 GGB 29200 Brest France
Univ Rennes CNRS IGDR UMR 6290 Rennes 35000 France
University Children's Hospital Zurich University of Zurich Zurich 8032 Switzerland
References provided by Crossref.org
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