ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.
Erratum issuedOpen access · bronzeAbstract read
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 52 papers.
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52citing papers in PubMed
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52 citing papers in PubMed, 97 citations in OpenAlex.
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- De novo protein-coding gene variants in developmental stuttering.Molecular psychiatry · 2026Article
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- New Insights into the Relation between Cognition, Behavior, and theMolecular syndromology · 2025Article
- Chromatin remodeling protein CHD4 regulates axon guidance of spiral ganglion neurons in the developing cochlea.bioRxiv : the preprint server for biology · 2025Article
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- It Takes a Village of Chromatin Remodelers to Regulate rDNA Expression.International journal of molecular sciences · 2025Review
- Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome.American journal of human genetics · 2025Article
- The chromatin remodeler ADNP regulates neurodevelopmental disorder risk genes and neocortical neurogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Generation and characterization of a mouse model of conditional Chd4 knockout in the endometrial epithelium.PloS one · 2025Article
- How does CHD4 slide nucleosomes?Biochemical Society transactions · 2024Review
- Whole-exome sequencing uncovers the genetic complexity of bicuspid aortic valve in families with early-onset complications.American journal of human genetics · 2024Article
- A Genotype/Phenotype Study ofGenes · 2024Article
- Genetic and phenotypic analysis of 225 Chinese children with developmental delay and/or intellectual disability using whole-exome sequencing.BMC genomics · 2024Article
- Validation of 3 Computer-Aided Facial Phenotyping Tools (DeepGestalt, GestaltMatcher, and D-Score): Comparative Diagnostic Accuracy Study.Journal of medical Internet research · 2024Article
- Human Genetics of Atrial Septal Defect.Advances in experimental medicine and biology · 2024Review
- SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.Brain : a journal of neurology · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
49 authors at 20 institutions in 9 countries.
Karin WeissThe Genetics Institute, Rambam Health Care Campus, Haifa, Israel. k_weiss@rambam.health.gov.il.ORCID http://orcid.org/0000-0003-0998-810X
Hayley P LazarEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.ORCID http://orcid.org/0000-0002-0065-9476
Alina KurolapThe Genetics Institute, Rambam Health Care Campus, Haifa, Israel.ORCID http://orcid.org/0000-0002-7005-3621
Ariel F MartinezMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-4109-1928
Tamar PapernaThe Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
Lior CohenGenetics Institute, Schneider Children's Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.ORCID http://orcid.org/0000-0003-2123-858X
Marie F SmelandDepartment of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
Sandra WhalenUF de génétique clinique, Centre de Référence Maladies Rares des Anomalies du développement et syndromes malformatifs, APHP, Hôpital Trousseau, Paris, France.
Solveig HeideAP-HP, Département de Génétique, Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs" Hôpital de la Pitié Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0002-4673-9762
Boris KerenAP-HP, Département de Génétique, Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs" Hôpital de la Pitié Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0001-6172-8247
Pauline TerhalDepartment of Genetics, Utrecht University Medical Center, Utrecht, the Netherlands.
Melita IrvingDepartment of Clinical Genetics, Guy's Hospital, London, UK.
Motoki TakakuEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.ORCID http://orcid.org/0000-0002-8652-2541
John D RobertsEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Robert M PetrovichEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Samantha A Schrier VerganoDivision of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.ORCID http://orcid.org/0000-0001-9194-0644
Amy KenneyDivision of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
Hanne HoveCentre for Rare Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Elizabeth DeCheneDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Shane C QuinonezDepartment of Pediatrics, Division of Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-8254-0216
Estelle ColinDepartment of Biochemistry and Genetics, University Hospital Angers, Angers, France.
Alban ZieglerDepartment of Biochemistry and Genetics, University Hospital Angers, Angers, France.ORCID http://orcid.org/0000-0003-0287-3561
Melissa RumpleBanner Child Neurology, Glendale, AZ, USA.
Mahim JainMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Danielle MonteilDepartment of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA, USA.ORCID http://orcid.org/0000-0002-9844-7817
Elizabeth R RoederDepartments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, USA.
Kimberly NugentDepartments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, USA.ORCID http://orcid.org/0000-0003-2161-3239
Arie van HaeringenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Michael GambelloDepartment of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA.
Avni SantaniDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-2871-4307
Līvija MedneDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Bryan KrockDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Cara M SkrabanDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Elaine H ZackaiDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Holly A DubbsDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Thomas SmolDepartment of Clinical Genetics, Lille University Hospital, CHU Lille, Lille, France.ORCID http://orcid.org/0000-0002-0119-5896
Jamal GhoumidDepartment of Clinical Genetics, Lille University Hospital, CHU Lille, Lille, France.ORCID http://orcid.org/0000-0002-7111-0050
Michael J ParkerSheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.
Michael WrightNorthern Genetics Service, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK.
Peter TurnpennyUniversity of Exeter Medical School, Clinical Genetics Royal Devon & Exeter Hospital, Exeter, UK.ORCID http://orcid.org/0000-0002-5947-0897
Jill Clayton-SmithInstitute of Evolution, Systems and Genomics, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Kay MetcalfeInstitute of Evolution, Systems and Genomics, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Hitoshi KurumizakaLaboratory of Structural Biology, Graduate School of Advanced Science & Engineering, Waseda University, Tokyo, Japan.
Bruce D GelbMindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0001-8527-5027
Hagit Baris FeldmanThe Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
Philippe M CampeauDepartment of Pediatrics, University of Montreal and CHU Sainte-Justine, Montreal, QC, Canada.ORCID http://orcid.org/0000-0001-9713-7107
Maximilian MuenkeMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-7719-6545
Paul A Wade *Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.ORCID http://orcid.org/0000-0002-6042-357X
Katherine Lachlan *Wessex Clinical Genetics Service, University Hospital Southampton NHS Trust. Department of Human Genetics and Genomic Medicine, Southampton University, Southampton, UK.
Children's Hospital of Philadelphia · USNational Institute of Environmental Health Sciences · USSorbonne Université · FRBaylor College of Medicine · USManchester Academic Health Science Centre · GBNational Institutes of Health · USRambam Health Care Campus · ILTechnion – Israel Institute of Technology · ILUniversité d'Angers · FRUniversité de Lille · FRCentre Hospitalier Universitaire Sainte-Justine · CAChild Health and Development Institute · USChildren's Hospital of The King's Daughters · USCopenhagen University Hospital · DKEastern Virginia Medical School · USEmory University · USGuy's Hospital · GBKennedy Krieger Institute · USLeiden University Medical Center · NLNaval Medical Center Portsmouth · US
Funding
Administrative Coordinating Center: Cardiovascular Development and Pediatric Cardiac Genomics ConsortiaU01HL131003 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI CNOTA, JAMES, OLLBERDING, NICHOLAS J · 2016 to 2024
$54.8MEukaryotic Transcriptional RegulationZIAES101965 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI WADE, PAUL A · 2009 to 2025
$40.9MProtein Expression FacilityZICES102487 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI PETROVICH, ROBERT · 2009 to 2025
$23.9MEukaryotic Transcriptional RegulationZ01ES101965 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI WADE, PAUL A · 2005 to 2008
$3.5MGenetics of Hypoplastic Left Heart SyndromeUM1HL128761 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI BERNSTEIN, DANIEL, SRIVASTAVA, DEEPAK · 2015 to 2019
$2.5MThe Genomic Basis of Congenital Heart Disease and Neurodevelopmental OutcomesUM1HL098147 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI NEWBURGER, JANE W., ROBERTS, AMY E · 2015 to 2019
$2.4MGenetics of conotruncal defects and associated neurodevelopmental outcomesUM1HL098123 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI GELB, BRUCE D · 2015 to 2019
$2.3MGenetics and genomics of congenital heart disease and associated neurodevelopmental abnormalitiesUM1HL098162 · NHLBI · YALE UNIVERSITY · PI BRUECKNER, MARTINA, GUPTA, ABHA RANI · 2015 to 2019
$2.2MBridging the Gap between Genomics and Clinical Outcomes in CHDUM1HL128711 · NHLBI · UNIVERSITY OF UTAH · PI TRISTANI-FIROUZI, MARTIN, YANDELL, MARK DOUGLAS · 2015 to 2019
$2.0MBig Omics Data Engine 2 SupercomputerS10OD026880 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI KOVATCH, PATRICIA · 2019 to 2019
$2.0MPediatric Heart Network Joint Heart Program ConsortiumUM1HL172717 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI Louis Bezold, James Cnota · 2024 to 2026
$1.3MDepartment of Health HICF-1009-003Intramural NIH HHS Z01 ES101965Intramural NIH HHS ZIA ES101965NHLBI NIH HHS U01 HL131003NHLBI NIH HHS UM1 HL098123NHLBI NIH HHS UM1 HL098147NHLBI NIH HHS UM1 HL098162NHLBI NIH HHS UM1 HL128711NHLBI NIH HHS UM1 HL128761NHLBI NIH HHS UM1 HL172717NIH HHS S10 OD026880Wellcome TrustWellcome Trust WT098051
Abstract
purposeSifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.
methodsWe collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.
resultsThe majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.
conclusionThe CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
Indexed as
Abnormalities, MultipleAdolescentAdultChildChild, PreschoolChromatin Assembly and DisassemblyDevelopmental DisabilitiesFemaleGenetic Association StudiesGenotypeHearing LossHeart Defects, CongenitalHumansInfantInfant, NewbornIntellectual DisabilityCHD4 protein, humanMi-2 Nucleosome Remodeling and Deacetylase ComplexTranscription Factors12p13.31ATPasechromatin remodelingintellectual disabilitymissense
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