npj Genomic Medicine (Dec 2021)
De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities
- Volkan Okur,
- Zefu Chen,
- Liesbeth Vossaert,
- Sandra Peacock,
- Jill Rosenfeld,
- Lina Zhao,
- Haowei Du,
- Emily Calamaro,
- Amanda Gerard,
- Sen Zhao,
- Jill Kelsay,
- Ashley Lahr,
- Chloe Mighton,
- Hillary M. Porter,
- Amy Siemon,
- Josh Silver,
- Shayna Svihovec,
- Chin-To Fong,
- Christina L. Grant,
- Jordan Lerner-Ellis,
- Kandamurugu Manickam,
- Suneeta Madan-Khetarpal,
- Shawn E. McCandless,
- Chantal F. Morel,
- G. Bradley Schaefer,
- Elizabeth M. Berry-Kravis,
- Ryan Gates,
- Natalia Gomez-Ospina,
- Guixing Qiu,
- Terry Jianguo Zhang,
- Zhihong Wu,
- Linyan Meng,
- Pengfei Liu,
- Daryl A. Scott,
- James R. Lupski,
- Christine M. Eng,
- Nan Wu,
- Bo Yuan
Affiliations
- Volkan Okur
- Department of Molecular and Human Genetics, Baylor College of Medicine
- 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
- Liesbeth Vossaert
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Sandra Peacock
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Jill Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Lina Zhao
- 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
- Haowei Du
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Emily Calamaro
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry
- Amanda Gerard
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Sen Zhao
- 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
- Jill Kelsay
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences
- Ashley Lahr
- Department of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC
- Chloe Mighton
- Institute of Health Policy, Management and Evaluation, University of Toronto
- Hillary M. Porter
- Rare Disease Institute, Children’s National Hospital
- Amy Siemon
- Nationwide Children’s Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine
- Josh Silver
- The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital
- Shayna Svihovec
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children’s Hospital Colorado
- Chin-To Fong
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry
- Christina L. Grant
- Rare Disease Institute, Children’s National Hospital
- Jordan Lerner-Ellis
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health
- Kandamurugu Manickam
- Nationwide Children’s Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine
- Suneeta Madan-Khetarpal
- Department of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC
- Shawn E. McCandless
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children’s Hospital Colorado
- Chantal F. Morel
- The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital
- G. Bradley Schaefer
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences
- Elizabeth M. Berry-Kravis
- Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center
- Ryan Gates
- Department of Pediatrics, Stanford University School of Medicine
- Natalia Gomez-Ospina
- Department of Pediatrics, Stanford University School of Medicine
- Guixing Qiu
- 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
- Terry Jianguo Zhang
- 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
- Zhihong Wu
- 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
- Linyan Meng
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Pengfei Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Daryl A. Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine
- James R. Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Christine M. Eng
- Baylor Genetics Laboratories
- Nan Wu
- 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
- Bo Yuan
- Department of Molecular and Human Genetics, Baylor College of Medicine
- DOI
- https://doi.org/10.1038/s41525-021-00268-8
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 10
Abstract
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.
