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

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

  • NPJ Genom Med. 2021 Dec 7;6(1):104. doi: 10.1038/s41525-021-00268-8.
Volkan Okur # 1 2,  Zefu Chen # 3 4,  Liesbeth Vossaert 1 2,  Sandra Peacock 1 2,  Jill Rosenfeld 1,  Lina Zhao 3 5,  Haowei Du 1,  Emily Calamaro 6,  Amanda Gerard 1 7,  Sen Zhao 3 5,  Jill Kelsay 8,  Ashley Lahr 9,  Chloe Mighton 10 11 12 13,  Hillary M Porter 14,  Amy Siemon 15,  Josh Silver 16 17,  Shayna Svihovec 18,  Chin-To Fong 6,  Christina L Grant 14,  Jordan Lerner-Ellis 12 13 19,  Kandamurugu Manickam 15,  Suneeta Madan-Khetarpal 9,  Shawn E McCandless 18,  Chantal F Morel 16 20,  G Bradley Schaefer 8,  Elizabeth M Berry-Kravis 21,  Ryan Gates 22,  Natalia Gomez-Ospina 22,  Guixing Qiu 3,  Terry Jianguo Zhang 3,  Zhihong Wu 3 5,  Linyan Meng 1 2,  Pengfei Liu 1 2,  Daryl A Scott 1 7,  James R Lupski 1 7 23 24,  Christine M Eng 2,  Nan Wu 25,  Bo Yuan 26 27 28 29
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 2 Baylor Genetics Laboratories, Houston, TX, 77021, USA.
  • 3 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.
  • 4 Graduate School of Peking Union Medical College, 100005, Beijing, China.
  • 5 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.
  • 6 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
  • 7 Texas Children's Hospital, Houston, TX, 77030, USA.
  • 8 Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA.
  • 9 Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
  • 10 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, M5T 3M6, Canada.
  • 11 Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, M5B 1A6, Canada.
  • 12 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, M5G 1X5, Canada.
  • 13 Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.
  • 14 Rare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.
  • 15 Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.
  • 16 The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
  • 17 Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • 18 Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.
  • 19 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • 20 Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • 21 Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL, 60612, USA.
  • 22 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 23 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 24 Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 25 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. [email protected].
  • 26 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. [email protected].
  • 27 Baylor Genetics Laboratories, Houston, TX, 77021, USA. [email protected].
  • 28 Seattle Children's Hospital, Seattle, WA, 98105, USA. [email protected].
  • 29 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, UW, 98105, USA. [email protected].
  • # Contributed equally.
PMID: 34876591 DOI: 10.1038/s41525-021-00268-8
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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