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 University Medical Centers Department of Clinical Genetics Amsterdam the Netherlands

Boston Children's Hospital Boston MA USA

Boston Children's Hospital Boston MA USA; Harvard Medical School Boston MA 02115 USA

Center for Integrative Genomics University of Lausanne Lausanne Switzerland

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 Endocrinology and Genetics University Clinic for Children's Diseases Medical Faculty University Sv Kiril i Metodij Skopje Republic of Macedonia

Department of Genetic Medicine and Development University of Geneva Geneva Switzerland

Department of Genetics University of Alabama at Birmingham Birmingham AL USA

Department of Human Genetics Amsterdam University Medical Centers VU University Amsterdam Amsterdam The Netherlands; Amsterdam Neuroscience Amsterdam The Netherlands

Department of Medical Sciences University of Torino 10126 Torino Italy

Department of Ophthalmology University of Lausanne Jules Gonin Eye Hospital Fondation Asile des Aveugles Lausanne Switzerland; Advanced Molecular Genetics and Genomics Disease Research and Treatment Centre Dow University of Health Sciences Karachi Pakistan

Department of Pediatrics and Inherited Metabolic Disorders General University Hospital and 1st faculty of Medicine Charles University Prague Czech Republic

Department of Pediatrics Division of Genetics and Metabolism University of Texas Southwestern Medical Center Dallas TX USA

Department of Pharmacology and Toxicology College of Pharmacy University of Utah Salt Lake City UT 84112 USA

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

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

Institute of Medical Genetics University of Zurich Schlieren 8952 Switzerland; University Children's Hospital Zurich University of Zurich Zurich 8032 Switzerland

Medical Genetics Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Medical Genetics Unit and Thalassemia Center San Luigi University Hospital University of Torino Orbassano Italy

Molecular Biotechnology and Health Sciences Department Università degli Studi di Torino via Quarello 15 10135 Torino Italy

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

Pathology and Laboratory Medicine Genomic Medicine Neurological and Pediatrics Institutes Cleveland Clinic Cleveland OH USA

Pediatrics and Medical Genetics University of Colorado Aurora CO USA

Research Unit for Rare Diseases Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Section of Genetics and Metabolism Department of Pediatrics University of Colorado Anschutz Medical Campus Aurora CO 80045 USA

Service de Génétique Clinique Centre de Référence Maladies Rares CLAD Ouest CHU Hôpital Sud Rennes France

Service de Génétique Moléculaire et Génomique CHU Rennes 35033 France; Univ Rennes CNRS IGDR UMR 6290 Rennes 35000 France

Service de Médecine Génomique des Maladies de Système et d'Organe Département Médico Universitaire BioPhyGen Hôpital Cochin APHP Université Paris Cité Paris France

Univ Brest Inserm EFS UMR 1078 GGB 29200 Brest France

Univ Brest Inserm EFS UMR 1078 GGB 29200 Brest France; Service de Génétique Médicale et Biologie de la Reproduction CHU de Brest Brest France; Centre de Référence Déficiences Intellectuelles de causes rares Brest France

Vanderbilt University Medical Center Nashville TN 37232 USA

See more in PubMed

Ropers H.H. Genetics of intellectual disability. Curr. Opin. Genet. Dev. 2008;18:241–250. doi: 10.1016/j.gde.2008.07.008. PubMed DOI

Cooper G.M., Coe B.P., Girirajan S., Rosenfeld J.A., Vu T.H., Baker C., Williams C., Stalker H., Hamid R., Hannig V., et al. A copy number variation morbidity map of developmental delay. Nat. Genet. 2011;43:838–846. doi: 10.1038/ng.909. PubMed DOI PMC

Srivastava S., Love-Nichols J.A., Dies K.A., Ledbetter D.H., Martin C.L., Chung W.K., Firth H.V., Frazier T., Hansen R.L., Prock L., et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet. Med. 2019;21:2413–2421. doi: 10.1038/S41436-019-0554-6. PubMed DOI PMC

Bamshad M.J., Nickerson D.A., Chong J.X. Mendelian gene discovery: fast and furious with no end in sight. Am. J. Hum. Genet. 2019;105:448–455. doi: 10.1016/J.AJHG.2019.07.011. PubMed DOI PMC

Hakimi M.-A., Dong Y., Lane W.S., Speicher D.W., Shiekhattar R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem. 2003;278:7234–7239. doi: 10.1074/jbc.M208992200. PubMed DOI

Shapson-Coe A., Valeiras B., Wall C., Rada C. Aicardi-Goutières Syndrome associated mutations of RNase H2B impair its interaction with ZMYM3 and the CoREST histone-modifying complex. PLoS One. 2019;14:e0213553. doi: 10.1371/JOURNAL.PONE.0213553. PubMed DOI PMC

Hu X., Shen B., Liao S., Ning Y., Ma L., Chen J., Lin X., Zhang D., Li Z., Zheng C., et al. Gene knockout of Zmym3 in mice arrests spermatogenesis at meiotic metaphase with defects in spindle assembly checkpoint. Cell Death Dis. 2017;8:e2910. doi: 10.1038/cddis.2017.228. PubMed DOI PMC

Leung J.W.C., Makharashvili N., Agarwal P., Chiu L.-Y., Pourpre R., Cammarata M.B., Cannon J.R., Sherker A., Durocher D., Brodbelt J.S., et al. ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair. Genes Dev. 2017;31:260–274. doi: 10.1101/gad.292516.116. PubMed DOI PMC

van der Maarel S.M., Scholten I.H., Huber I., Philippe C., Suijkerbuijk R.F., Gilgenkrantz S., Kere J., Cremers F.P., Ropers H.H. Cloning and characterization of DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1. Hum. Mol. Genet. 1996;5:887–897. PubMed

Philips A.K., Sirén A., Avela K., Somer M., Peippo M., Ahvenainen M., Doagu F., Arvio M., Kääriäinen H., Van Esch H., et al. X-exome sequencing in Finnish families with Intellectual Disability - Four novel mutations and two novel syndromic phenotypes. Orphanet J. Rare Dis. 2014;9:49. doi: 10.1186/1750-1172-9-49. PubMed DOI PMC

Boycott K.M., Azzariti D.R., Hamosh A., Rehm H.L. Seven years since the launch of the matchmaker exchange: the evolution of genomic matchmaking. Hum. Mutat. 2022;43:659–667. doi: 10.1002/HUMU.24373. PubMed DOI PMC

Hamosh A., Wohler E., Martin R., Griffith S., Rodrigues E.d.S., Antonescu C., Doheny K.F., Valle D., Sobreira N. The impact of GeneMatcher on international data sharing and collaboration. Hum. Mutat. 2022;43:668–673. doi: 10.1002/HUMU.24350. PubMed DOI PMC

Osmond M., Hartley T., Johnstone B., Andjic S., Girdea M., Gillespie M., Buske O., Dumitriu S., Koltunova V., Ramani A., et al. PhenomeCentral: 7 years of rare disease matchmaking. Hum. Mutat. 2022;43:674–681. doi: 10.1002/HUMU.24348. PubMed DOI

Jumper J., Evans R., Pritzel A., Green T., Figurnov M., Ronneberger O., Tunyasuvunakool K., Bates R., Žídek A., Potapenko A., et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–589. doi: 10.1038/S41586-021-03819-2. PubMed DOI PMC

Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., Ferrin T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. doi: 10.1002/JCC.20084. PubMed DOI

Rossi Sebastiano M., Ermondi G., Hadano S., Caron G. AI-based protein structure databases have the potential to accelerate rare diseases research: AlphaFoldDB and the case of IAHSP/Alsin. Drug Discov. Today. 2022;27:1652–1660. doi: 10.1016/J.DRUDIS.2021.12.018. PubMed DOI

Savic D., Partridge E.C., Newberry K.M., Smith S.B., Meadows S.K., Roberts B.S., Mackiewicz M., Mendenhall E.M., Myers R.M. CETCh-seq: CRISPR epitope tagging ChIP-seq of DNA-binding proteins. Genome Res. 2015;25:1581–1589. doi: 10.1101/GR.193540.115. PubMed DOI PMC

Meadows S.K., Brandsmeier L.A., Newberry K.M., Betti M.J., Nesmith A.S., Mackiewicz M., Partridge E.C., Mendenhall E.M., Myers R.M. Epitope tagging ChIP-seq of DNA binding proteins using CETCh-seq. Methods Mol. Biol. 2020;2117:3–34. doi: 10.1007/978-1-0716-0301-7_1/COVER. PubMed DOI

Kharchenko P.V., Tolstorukov M.Y., Park P.J. Design and analysis of ChIP-seq experiments for DNA-binding proteins. Nat. Biotechnol. 2008;26:1351–1359. doi: 10.1038/nbt.1508. PubMed DOI PMC

Li Q., Brown J.B., Huang H., Bickel P.J. Measuring Reproducibility of High-Throughput Experiments. Ann. Appl. Stat. 2011;5:1752–1779. doi: 10.1214/11-AOAS466. DOI

Landt S.G., Marinov G.K., Kundaje A., Kheradpour P., Pauli F., Batzoglou S., Bernstein B.E., Bickel P., Brown J.B., Cayting P., et al. ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Res. 2012;22:1813–1831. doi: 10.1101/GR.136184.111. PubMed DOI PMC

Lun A.T.L., Smyth G.K. csaw: a Bioconductor package for differential binding analysis of ChIP-seq data using sliding windows. Nucleic Acids Res. 2016;44:e45. doi: 10.1093/NAR/GKV1191. PubMed DOI PMC

Kircher M., Witten D.M., Jain P., O’Roak B.J., Cooper G.M., Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 2014;46:310–315. doi: 10.1038/ng.2892. PubMed DOI PMC

Cooper G.M., Stone E.A., Asimenos G., NISC Comparative Sequencing Program. Green E.D., Batzoglou S., Sidow A. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15:901–913. doi: 10.1101/GR.3577405. PubMed DOI PMC

Connaughton D.M., Dai R., Owen D.J., Marquez J., Mann N., Graham-Paquin A.L., Nakayama M., Coyaud E., Laurent E.M.N., St-Germain J.R., et al. Mutations of the transcriptional corepressor ZMYM2 cause syndromic urinary tract malformations. Am. J. Hum. Genet. 2020;107:727–742. doi: 10.1016/J.AJHG.2020.08.013. PubMed DOI PMC

Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., O’Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., et al. Analysis of protein-coding genetic variation in 60, 706 humans. Nature. 2016;536:285–291. doi: 10.1038/nature19057. PubMed DOI PMC

Bertelsen B., Tümer Z., Ravn K. Three new loci for determining x chromosome inactivation patterns. J. Mol. Diagn. 2011;13:537–540. doi: 10.1016/J.JMOLDX.2011.05.003. PubMed DOI PMC

Machado F.B., Machado F.B., Faria M.A., Lovatel V.L., Alves Da Silva A.F., Radic C.P., De Brasi C.D., Rios Á.F.L., de Sousa Lopes S.M.C., da Silveira L.S., et al. 5meCpG epigenetic marks neighboring a primate-conserved core promoter short tandem repeat indicate X-chromosome inactivation. PLoS One. 2014;9:e103714. doi: 10.1371/JOURNAL.PONE.0103714. PubMed DOI PMC

Mariani V., Biasini M., Barbato A., Schwede T. lDDT: a local superposition-free score for comparing protein structures and models using distance difference tests. Bioinformatics. 2013;29:2722–2728. doi: 10.1093/BIOINFORMATICS/BTT473. PubMed DOI PMC

Kumar M., Michael S., Alvarado-Valverde J., Mészáros B., Sámano-Sánchez H., Zeke A., Dobson L., Lazar T., Örd M., Nagpal A., et al. The Eukaryotic Linear Motif resource: 2022 release. Nucleic Acids Res. 2022;50:D497–D508. doi: 10.1093/NAR/GKAB975. PubMed DOI PMC

Johnson D.S., Mortazavi A., Myers R.M., Wold B. Genome-wide mapping of in vivo protein-DNA interactions. Science. 2007;316:1497–1502. doi: 10.1126/SCIENCE.1141319/SUPPL_FILE/JOHNSON.SOM-5-30.PDF. PubMed DOI

Petrovski S., Wang Q., Heinzen E.L., Allen A.S., Goldstein D.B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9:e1003709. doi: 10.1371/journal.pgen.1003709. PubMed DOI PMC

Landrum M.J., Lee J.M., Benson M., Brown G., Chao C., Chitipiralla S., Gu B., Hart J., Hoffman D., Hoover J., et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:D862–D868. doi: 10.1093/nar/gkv1222. PubMed DOI PMC

Chong J.X., Yu J.H., Lorentzen P., Park K.M., Jamal S.M., Tabor H.K., Rauch A., Saenz M.S., Boltshauser E., Patterson K.E., et al. Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet. Med. 2016;18:788–795. doi: 10.1038/GIM.2015.161. PubMed DOI PMC

Kumble S., Levy A.M., Punetha J., Gao H., Ah Mew N., Anyane-Yeboa K., Benke P.J., Berger S.M., Bjerglund L., Campos-Xavier B., et al. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder. Hum. Mutat. 2022;43:266–282. doi: 10.1002/HUMU.24308. PubMed DOI

ENCODE Project Consortium. Kundaje A., Aldred S.F., Collins P.J., Davis C.A., Doyle F., Epstein C.B., Frietze S., Harrow J., Kaul R., et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74. doi: 10.1038/NATURE11247. PubMed DOI PMC

Nasser J., Bergman D.T., Fulco C.P., Guckelberger P., Doughty B.R., Patwardhan T.A., Jones T.R., Nguyen T.H., Ulirsch J.C., Lekschas F., et al. Genome-wide enhancer maps link risk variants to disease genes. Nature. 2021;593:238–243. doi: 10.1038/S41586-021-03446-X. PubMed DOI PMC

Gupta A.R., Pirruccello M., Cheng F., Kang H.J., Fernandez T.V., Baskin J.M., Choi M., Liu L., Ercan-Sencicek A.G., Murdoch J.D., et al. Rare deleterious mutations of the gene EFR3A in autism spectrum disorders. Mol. Autism. 2014;5:31. doi: 10.1186/2040-2392-5-31. PubMed DOI PMC

Samocha K.E., Robinson E.B., Sanders S.J., Stevens C., Sabo A., McGrath L.M., Kosmicki J.A., Rehnström K., Mallick S., Kirby A., et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 2014;46:944–950. doi: 10.1038/ng.3050. PubMed DOI PMC