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.

Details

Title
De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities
Author
Okur Volkan 1 ; Chen Zefu 2 ; Vossaert Liesbeth 1 ; Peacock, Sandra 1 ; Rosenfeld, Jill 3   VIAFID ORCID Logo  ; Zhao, Lina 4 ; Du Haowei 3 ; Calamaro Emily 5 ; Gerard, Amanda 6 ; Sen, Zhao 4 ; Kelsay, Jill 7 ; Lahr, Ashley 8 ; Mighton Chloe 9 ; Porter, Hillary M 10   VIAFID ORCID Logo  ; Siemon, Amy 11 ; Silver, Josh 12 ; Svihovec Shayna 13   VIAFID ORCID Logo  ; Chin-To, Fong 5 ; Grant, Christina L 10   VIAFID ORCID Logo  ; Lerner-Ellis, Jordan 14 ; Manickam Kandamurugu 11 ; Madan-Khetarpal Suneeta 8 ; McCandless, Shawn E 15 ; Morel, Chantal F 16 ; Bradley, Schaefer G 7 ; Berry-Kravis, Elizabeth M 17 ; Gates, Ryan 18 ; Gomez-Ospina, Natalia 18 ; Qiu Guixing 19 ; Zhang, Terry Jianguo 19 ; Wu, Zhihong 4 ; Meng Linyan 1 ; Liu, Pengfei 1 ; Scott, Daryl A 6   VIAFID ORCID Logo  ; Lupski James R 20   VIAFID ORCID Logo  ; Eng, Christine M 21 ; Wu, Nan 19   VIAFID ORCID Logo  ; Yuan, Bo 22   VIAFID ORCID Logo 

1  Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Baylor Genetics Laboratories, Houston, USA (GRID:grid.510928.7) 
2  Peking Union Medical College and Chinese Academy of Medical Sciences, 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, Beijing, China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839); Graduate School of Peking Union Medical College, Beijing, China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839) 
3  Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
4  Peking Union Medical College and Chinese Academy of Medical Sciences, 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, Beijing, China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839); Peking Union Medical College and Chinese Academy of Medical Sciences, Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839) 
5  University of Rochester School of Medicine and Dentistry, Department of Pediatrics, Rochester, USA (GRID:grid.412750.5) (ISNI:0000 0004 1936 9166) 
6  Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Texas Children’s Hospital, Houston, USA (GRID:grid.416975.8) (ISNI:0000 0001 2200 2638) 
7  University of Arkansas for Medical Sciences, Section of Genetics and Metabolism, Little Rock, USA (GRID:grid.241054.6) (ISNI:0000 0004 4687 1637) 
8  Children’s Hospital of Pittsburgh of UPMC, Department of Medical Genetics, Pittsburgh, USA (GRID:grid.239553.b) (ISNI:0000 0000 9753 0008) 
9  University of Toronto, Institute of Health Policy, Management and Evaluation, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); Unity Health Toronto, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada (GRID:grid.415502.7); Mount Sinai Hospital, Sinai Health, Department of Pathology and Laboratory Medicine, Toronto, Canada (GRID:grid.416166.2) (ISNI:0000 0004 0473 9881); Sinai Health, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada (GRID:grid.492573.e) 
10  Children’s National Hospital, Rare Disease Institute, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586) 
11  Nationwide Children’s Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476) 
12  University Health Network and Mount Sinai Hospital, The Fred A. Litwin Family Centre in Genetic Medicine, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428); University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
13  University of Colorado Anschutz Medical Campus, and Children’s Hospital Colorado, Department of Pediatrics, Aurora, USA (GRID:grid.17063.33) 
14  Mount Sinai Hospital, Sinai Health, Department of Pathology and Laboratory Medicine, Toronto, Canada (GRID:grid.416166.2) (ISNI:0000 0004 0473 9881); Sinai Health, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada (GRID:grid.492573.e); University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
15  University of Colorado Anschutz Medical Campus, and Children’s Hospital Colorado, Department of Pediatrics, Aurora, USA (GRID:grid.239553.b) 
16  University Health Network and Mount Sinai Hospital, The Fred A. Litwin Family Centre in Genetic Medicine, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428); University of Toronto, Department of Medicine, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
17  Rush University Medical Center, Departments of Pediatrics, Neurological Sciences, and Biochemistry, Chicago, USA (GRID:grid.240684.c) (ISNI:0000 0001 0705 3621) 
18  Stanford University School of Medicine, Department of Pediatrics, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
19  Peking Union Medical College and Chinese Academy of Medical Sciences, 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, Beijing, China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839) 
20  Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Texas Children’s Hospital, Houston, USA (GRID:grid.416975.8) (ISNI:0000 0001 2200 2638); Baylor College of Medicine, Human Genome Sequencing Center, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Baylor College of Medicine, Department of Pediatrics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
21  Baylor Genetics Laboratories, Houston, USA (GRID:grid.510928.7) 
22  Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Baylor Genetics Laboratories, Houston, USA (GRID:grid.510928.7); Seattle Children’s Hospital, Seattle, USA (GRID:grid.240741.4) (ISNI:0000 0000 9026 4165); University of Washington, Department of Laboratory Medicine and Pathology, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20567944
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41525-021-00268-8
ProQuest document ID
2607468042
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.