De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.

Journal

NPJ genomic medicine
ISSN: 2056-7944
Titre abrégé: NPJ Genom Med
Pays: England
ID NLM: 101685193

Informations de publication

Date de publication:
07 Dec 2021
Historique:
received: 20 04 2021
accepted: 28 10 2021
entrez: 8 12 2021
pubmed: 9 12 2021
medline: 9 12 2021
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41525-021-00268-8 PMID: 34876591 PMC: PMC8651650
pubmed: 34876591
doi: 10.1038/s41525-021-00268-8
pii: 10.1038/s41525-021-00268-8
pmc: PMC8651650
doi:

Types de publication

Journal Article

Langues

eng

Pagination

104

Subventions

Organisme : Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)
ID : 7191007
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81930068 and 81772299
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)
ID : JQ20032
Organisme : Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre)
ID : FRN: 135790
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81822030 and 82072391
Organisme : Chinese Academy of Medical Sciences (CAMS)
ID : 2019PT320025
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : Chinese Academy of Medical Sciences (CAMS)
ID : 2020-I2M-C&T-B-030
Organisme : U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
ID : UM1HG006542
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81772301 and 81972132

Informations de copyright

© 2021. The Author(s).

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Auteurs

Volkan Okur (V)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Baylor Genetics Laboratories, Houston, TX, 77021, USA.

Zefu Chen (Z)

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.
Graduate School of Peking Union Medical College, 100005, Beijing, China.

Liesbeth Vossaert (L)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Baylor Genetics Laboratories, Houston, TX, 77021, USA.

Sandra Peacock (S)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Baylor Genetics Laboratories, Houston, TX, 77021, USA.

Jill Rosenfeld (J)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
ORCID: 0000-0001-5664-7987

Lina Zhao (L)

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.
Medical Research Center, 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 Du (H)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Emily Calamaro (E)

Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.

Amanda Gerard (A)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Texas Children's Hospital, Houston, TX, 77030, USA.

Sen Zhao (S)

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.
Medical Research Center, 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 Kelsay (J)

Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA.

Ashley Lahr (A)

Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.

Chloe Mighton (C)

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, M5T 3M6, Canada.
Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, M5B 1A6, Canada.
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, M5G 1X5, Canada.
Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.

Hillary M Porter (HM)

Rare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.
ORCID: 0000-0002-9554-8006

Amy Siemon (A)

Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.

Josh Silver (J)

The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.

Shayna Svihovec (S)

Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.
ORCID: 0000-0002-9359-1916

Chin-To Fong (CT)

Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.

Christina L Grant (CL)

Rare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.
ORCID: 0000-0002-0627-4614

Jordan Lerner-Ellis (J)

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, M5G 1X5, Canada.
Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.

Kandamurugu Manickam (K)

Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.

Suneeta Madan-Khetarpal (S)

Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.

Shawn E McCandless (SE)

Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.

Chantal F Morel (CF)

The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.

G Bradley Schaefer (GB)

Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA.

Elizabeth M Berry-Kravis (EM)

Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL, 60612, USA.

Ryan Gates (R)

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Natalia Gomez-Ospina (N)

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Guixing Qiu (G)

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.

Terry Jianguo Zhang (TJ)

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.

Zhihong Wu (Z)

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.
Medical Research Center, 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 Meng (L)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Baylor Genetics Laboratories, Houston, TX, 77021, USA.

Pengfei Liu (P)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Baylor Genetics Laboratories, Houston, TX, 77021, USA.

Daryl A Scott (DA)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Texas Children's Hospital, Houston, TX, 77030, USA.
ORCID: 0000-0003-1460-5169

James R Lupski (JR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Texas Children's Hospital, Houston, TX, 77030, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
ORCID: 0000-0001-9907-9246

Christine M Eng (CM)

Baylor Genetics Laboratories, Houston, TX, 77021, USA.

Nan Wu (N)

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. dr.wunan@pumch.cn.
ORCID: 0000-0002-9429-2889

Bo Yuan (B)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. Bo.Yuan@seattlechildrens.org.
Baylor Genetics Laboratories, Houston, TX, 77021, USA. Bo.Yuan@seattlechildrens.org.
Seattle Children's Hospital, Seattle, WA, 98105, USA. Bo.Yuan@seattlechildrens.org.
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, UW, 98105, USA. Bo.Yuan@seattlechildrens.org.
ORCID: 0000-0001-7278-5116

Classifications MeSH