ArticleNPJ genomic medicine2021
De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.
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Article in NPJ genomic medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 26 citations in OpenAlex.
- A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental/neurodegenerative syndrome demonstrates the role of histone H3.3 in chromatin dynamics, neuronal differentiation, and maturation.Journal of translational medicine · 2026Article
- Paroxysmal Dyskinesia with a Novel Variant in the Histone 3 Family 3B (H3-3B) Gene.Movement disorders clinical practice · 2026Article
- Article
- Histone variants: expanding the epigenetic potential of neurons one amino acid at a time.Trends in biochemical sciences · 2025Review
- Molecular and clinical aspects of histone-related disorders.Human genomics · 2025Review
- Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders.iScience · 2025Review
- Multifunctional histone variants in genome function.Nature reviews. Genetics · 2025Review
- The ortholog of human DNAJC9 promotes histone H3-H4 degradation and is counteracted by Asf1 in fission yeast.Nucleic acids research · 2025Article
- Leveraging cancer mutation data to inform the pathogenicity classification of germline missense variants.PLoS genetics · 2025Article
- Neonatal myoclonus in Bryant-Li-Bhoj syndrome associated with a novel H3F3A variant.Human genome variation · 2024Article
- Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.European journal of human genetics : EJHG · 2024Article
- Fatty Acid Amide Hydrolase and Cannabinoid Receptor Type 1 Genes Regulation is Modulated by Social Isolation in Rats.Neurochemical research · 2024Article
- Histone 3.3-related chromatinopathy: missense variants throughout H3-3A and H3-3B cause a range of functional consequences across species.Human genetics · 2024Review
- Gatad2b, associated with the neurodevelopmental syndrome GAND, plays a critical role in neurodevelopment and cortical patterning.Translational psychiatry · 2024Article
- Trapping of yFACT at 3' ends of genes is not a universal characteristic of yeast versions of Bryant-Li-Bhoj syndrome histone H3 mutants.microPublication biology · 2024Article
- The cell-cycle choreography of H3 variants shapes the genome.Molecular cell · 2023Review
- Involvement of the H3.3 Histone Variant in the Epigenetic Regulation of Gene Expression in the Nervous System, in Both Physiological and Pathological Conditions.International journal of molecular sciences · 2023Review
- Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration.Cell · 2023Article
- Epigenetic equilibrium in chromatinopathies: network instability in neurodevelopment.Frontiers in neurologyReview
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Authors and funding
38 authors at 12 institutions in 3 countries.
Volkan Okur *Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Zefu Chen *Department of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
Liesbeth VossaertDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Sandra PeacockDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Jill RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.ORCID http://orcid.org/0000-0001-5664-7987
Lina ZhaoDepartment of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
Haowei DuDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Emily CalamaroDepartment of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
Amanda GerardDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Sen ZhaoDepartment of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
Jill KelsaySection of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA.
Ashley LahrDepartment of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
Chloe MightonInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, M5T 3M6, Canada.
Hillary M PorterRare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.ORCID http://orcid.org/0000-0002-9554-8006
Amy SiemonNationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.
Josh SilverThe Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
Shayna SvihovecDepartment of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.ORCID http://orcid.org/0000-0002-9359-1916
Chin-To FongDepartment of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
Christina L GrantRare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.ORCID http://orcid.org/0000-0002-0627-4614
Jordan Lerner-EllisDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, M5G 1X5, Canada.
Kandamurugu ManickamNationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.
Suneeta Madan-KhetarpalDepartment of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
Shawn E McCandlessDepartment of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.
Chantal F MorelThe Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
G Bradley SchaeferSection of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA.
Elizabeth M Berry-KravisDepartments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL, 60612, USA.
Ryan GatesDepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Natalia Gomez-OspinaDepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Guixing QiuDepartment of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
Terry Jianguo ZhangDepartment of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
Zhihong WuDepartment of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
Linyan MengDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Pengfei LiuDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Daryl A ScottDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.ORCID http://orcid.org/0000-0003-1460-5169
James R LupskiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.ORCID http://orcid.org/0000-0001-9907-9246
Christine M EngBaylor Genetics Laboratories, Houston, TX, 77021, USA.
Nan WuDepartment of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China. dr.wunan@pumch.cn.ORCID http://orcid.org/0000-0002-9429-2889
Bo YuanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. Bo.Yuan@seattlechildrens.org.ORCID http://orcid.org/0000-0001-7278-5116
Baylor College of Medicine · USChinese Academy of Medical Sciences & Peking Union Medical College · CNMount Sinai Hospital · CAChildren's Hospital Colorado · USChildren's Hospital of Pittsburgh · USChildren's National · USNationwide Children's Hospital · USStanford University · USUniversity of Arkansas for Medical Sciences · USUniversity of Rochester · USBaylor Genetics · USRush University Medical Center · US
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MBaylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MChinese Academy of Medical Sciences (CAMS) 2019PT320025Chinese Academy of Medical Sciences (CAMS) 2020-I2M-C&T-B-030Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre) FRN: 135790National Natural Science Foundation of China (National Science Foundation of China) 81772301 and 81972132National Natural Science Foundation of China (National Science Foundation of China) 81822030 and 82072391National Natural Science Foundation of China (National Science Foundation of China) 81930068 and 81772299Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation) 7191007Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation) JQ20032NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG006542NHGRI NIH HHS UM1 HG008900U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) UM1HG006542
Abstract
The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.
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