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De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.
Okur, Volkan; Chen, Zefu; Vossaert, Liesbeth; Peacock, Sandra; Rosenfeld, Jill; Zhao, Lina; Du, Haowei; Calamaro, Emily; Gerard, Amanda; Zhao, Sen; Kelsay, Jill; Lahr, Ashley; Mighton, Chloe; Porter, Hillary M; Siemon, Amy; Silver, Josh; Svihovec, Shayna; Fong, Chin-To; Grant, Christina L; Lerner-Ellis, Jordan; Manickam, Kandamurugu; Madan-Khetarpal, Suneeta; McCandless, Shawn E; Morel, Chantal F; Schaefer, G Bradley; Berry-Kravis, Elizabeth M; Gates, Ryan; Gomez-Ospina, Natalia; Qiu, Guixing; Zhang, Terry Jianguo; Wu, Zhihong; Meng, Linyan; Liu, Pengfei; Scott, Daryl A; Lupski, James R; Eng, Christine M; Wu, Nan; Yuan, Bo.
Afiliación
  • Okur V; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Chen Z; Baylor Genetics Laboratories, Houston, TX, 77021, USA.
  • Vossaert 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
  • Peacock S; Graduate School of Peking Union Medical College, 100005, Beijing, China.
  • Rosenfeld J; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Zhao L; Baylor Genetics Laboratories, Houston, TX, 77021, USA.
  • Du H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Calamaro E; Baylor Genetics Laboratories, Houston, TX, 77021, USA.
  • Gerard A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 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
  • Kelsay J; 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.
  • Lahr A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Mighton C; Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
  • Porter HM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • Siemon A; Texas Children's Hospital, Houston, TX, 77030, USA.
  • Silver J; 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
  • Svihovec S; 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.
  • Fong CT; Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA.
  • Grant CL; Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
  • Lerner-Ellis J; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, M5T 3M6, Canada.
  • Manickam K; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, M5B 1A6, Canada.
  • Madan-Khetarpal S; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, M5G 1X5, Canada.
  • McCandless SE; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.
  • Morel CF; Rare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.
  • Schaefer GB; Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.
  • Berry-Kravis EM; The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
  • Gates R; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Gomez-Ospina N; Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.
  • Qiu G; Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
  • Zhang TJ; Rare Disease Institute, Children's National Hospital, Washington, DC, 20010, USA.
  • Wu Z; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON, M5G 1X5, Canada.
  • Meng L; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.
  • Liu P; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Scott DA; Nationwide Children's Hospital (NCH) and The Ohio State University College of Medicine Section of Genetic and Genomic Medicine, Columbus, OH, 43205, USA.
  • Lupski JR; Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
  • Eng CM; Department of Pediatrics, University of Colorado Anschutz Medical Campus, and Children's Hospital Colorado, Aurora, CO, 80045, USA.
  • Wu N; The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, M5T 3L9, Canada.
  • Yuan B; Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
NPJ Genom Med ; 6(1): 104, 2021 Dec 07.
Article en En | MEDLINE | ID: mdl-34876591
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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Revista: NPJ Genom Med Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Revista: NPJ Genom Med Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos