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De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations3.35 MB
Published VersionCC BY-NC-ND V4.0, Open Access
Journal article
De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations
Genetics in Medicine, Vol.24(9), pp.1952-1966
2022
PMID: 35916866
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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 Drosophila ZMYND8 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.
Details
- Title
- De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations
- Authors
- Kerith-Rae Dias (Author) - Neuroscience Research AustraliaColleen M. Carlston (Author) - Harvard Medical SchoolLaura E.R. Blok (Author) - Radboud University Medical CenterLachlan De Hayr (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - LegacyUrwah Nawaz (Author) - The University of AdelaideCarey-Anne Evans (Author) - Neuroscience Research AustraliaPinar Bayrak-Toydemir (Author) - University of UtahStephanie Htun (Author) - University of California San Francisco Medical CenterYing Zhu (Author) - Prince of Wales HospitalAlan Ma (Author) - UNSW SydneySally Ann Lynch (Author) - Temple Street Children's University HospitalCatherine Moorwood (Author) - Royal Devon & Exeter NHS Foundation TrustKaren Stals (Author) - Royal Devon & Exeter NHS Foundation TrustSian Ellard (Author) - Royal Devon & Exeter NHS Foundation TrustMatthew N. Bainbridge (Author)Jennifer Friedman (Author) - University of California San Diego Medical CenterJohn G Pappas (Author) - New York University School of MedicineJessica Douglas (Author) - Boston Children's HospitalRabin Rabin (Author) - New York University School of MedicineTheodore E Wilson (Author) - Indiana University School of Medicine - LafayetteCatherine B Nowak (Author) - Boston Children's HospitalMaria J Guillen Sacoto (Author)Timothy Blake Palculict (Author)Edwin P Kirk (Author) - UNSW SydneyJason R Pinner (Author) - UNSW SydneyMatthew Edwards (Author) - Western Sydney UniversityFrancesca Montanari (Author) - University of BolognaClaudio Graziano (Author) - University of BolognaTommaso Pippucci (Author) - University of BolognaBri Dingmann (Author) - Seattle Children's HospitalIan Glass (Author) - Seattle Children's HospitalHeather C Mefford (Author) - St. Jude Children's Research HospitalTakeyoshi Shimoji (Author)Toshimitsu Suzuki (Author) - Nagoya City University HospitalKazuhiro Yamakawa (Author) - Nagoya City UniversityHaley Streff (Author) - Baylor College of MedicineChristian P Schaaf (Author) - Heidelberg UniversityAnne M Slavotinek (Author) - University of California, San FranciscoIrina Voineagu (Author) - UNSW SydneyJohn C Carey (Author) - University of Utah Health CareMichael F Buckley (Author) - Prince of Wales HospitalAnnette Schenck (Author) - Radboud University Medical CenterRobert Harvey (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - LegacyTony Roscioli (Author) - UNSW Sydney
- Publication details
- Genetics in Medicine, Vol.24(9), pp.1952-1966
- Publisher
- Elsevier Inc.
- Date published
- 2022
- DOI
- 10.1016/j.gim.2022.06.001
- ISSN
- 1530-0366; 1098-3600
- PMID
- 35916866
- Copyright note
- © 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- Grant note
- Radboudumc junior researcher fellowship to L.E.R.B. and A.S. and a personal grant from The Netherlands Organisation for Health Research and Development (ZonMw Vici, 09150181910022) to A.S.
- Organisation Unit
- School of Health - Biomedicine; School of Health; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99659497102621
- Output Type
- Journal article
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