De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations.

Autor:	Dias KR; Neuroscience Research Australia, Sydney, New South Wales, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia., Carlston CM; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Blok LER; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands., De Hayr L; School of Health and Behavioural Sciences, University of the Sunshine Coast, Maroochydore, Queensland, Australia; Sunshine Coast Health Institute, Birtinya, Queensland, Australia., Nawaz U; Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Evans CA; Neuroscience Research Australia, Sydney, New South Wales, Australia; New South Wales Health Pathology, Randwick Genomics Laboratory, Prince of Wales Hospital, Sydney, New South Wales, Australia., Bayrak-Toydemir P; Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT; Molecular Genomics, ARUP Laboratories, University of Utah School of Medicine, University of Utah, Salt Lake City, UT., Htun S; Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA., Zhu Y; New South Wales Health Pathology, Randwick Genomics Laboratory, Prince of Wales Hospital, Sydney, New South Wales, Australia., Ma A; Department of Clinical Genetics, Children's Hospital Westmead, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia; Specialty of Genomic Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia., Lynch SA; Department of Clinical Genetics, Temple Street Children's University Hospital, Dublin, Ireland., Moorwood C; Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom., Stals K; Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom., Ellard S; Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom., Bainbridge MN; Rady Children's Institute of Genomic Medicine, Rady Children's Hospital, San Diego, CA., Friedman J; Rady Children's Institute of Genomic Medicine, Rady Children's Hospital, San Diego, CA; Departments of Neurosciences and Pediatrics, University of California San Diego, San Diego, CA., Pappas JG; Department of Pediatrics, Clinical Genetic Services, NYU Grossman School of Medicine, NYU Langone Health, New York, NY., Rabin R; Department of Pediatrics, Clinical Genetic Services, NYU Grossman School of Medicine, NYU Langone Health, New York, NY., Nowak CB; The Feingold Center for Children, Boston Children's Hospital, Harvard Medical School, Boston, MA., Douglas J; The Feingold Center for Children, Boston Children's Hospital, Harvard Medical School, Boston, MA., Wilson TE; Department of Medical & Molecular Genetics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN., Guillen Sacoto MJ; GeneDx, Gaithersburg, MD., Mullegama SV; GeneDx, Gaithersburg, MD., Palculict TB; GeneDx, Gaithersburg, MD., Kirk EP; New South Wales Health Pathology, Randwick Genomics Laboratory, Prince of Wales Hospital, Sydney, New South Wales, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia., Pinner JR; School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia., Edwards M; Hunter Genetics, Hunter New England Health, New Lambton, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia., Montanari F; U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Graziano C; U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Pippucci T; U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Dingmann B; Medical Genetics Department, Seattle Children's Hospital, Seattle, WA., Glass I; Medical Genetics Department, Seattle Children's Hospital, Seattle, WA., Mefford HC; Center for Pediatric Neurological Disease Research, St. Jude Research, St. Jude Children's Hospital, Memphis, TN., Shimoji T; Department of Neurosurgery, Okinawa Pref. Nanbu Medical Center and Children's Medical Center, Okinawa, Japan; Okinawa Central Hospital, Okinawa, Japan., Suzuki T; Department of Neurodevelopmental Disorder Genetics, Institute of Brain Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan., Yamakawa K; Department of Neurodevelopmental Disorder Genetics, Institute of Brain Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan., Streff H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX., Schaaf CP; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Institute of Human Genetics, Heidelberg University, Heidelberg University Hospital, Heidelberg, Germany., Slavotinek AM; Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA., Voineagu I; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia., Carey JC; Division of Medical Genetics, Department of Pediatrics, University of Utah Health, Salt Lake City, UT., Buckley MF; New South Wales Health Pathology, Randwick Genomics Laboratory, Prince of Wales Hospital, Sydney, New South Wales, Australia., Schenck A; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands., Harvey RJ; School of Health and Behavioural Sciences, University of the Sunshine Coast, Maroochydore, Queensland, Australia; Sunshine Coast Health Institute, Birtinya, Queensland, Australia., Roscioli T; Neuroscience Research Australia, Sydney, New South Wales, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia; New South Wales Health Pathology, Randwick Genomics Laboratory, Prince of Wales Hospital, Sydney, New South Wales, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia. Electronic address: tony.roscioli@health.nsw.gov.au.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Sep; Vol. 24 (9), pp. 1952-1966. Date of Electronic Publication: 2022 Aug 01.
DOI:	10.1016/j.gim.2022.06.001
Abstrakt:	Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability. Competing Interests: Conflict of Interest S.V.M., T.B.P., and M.J.G.S. are employees of GeneDx, Inc. All other authors declare no conflicts of interest. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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