Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author:

Bryant Laura1ORCID,Li Dong1ORCID,Cox Samuel G.2,Marchione Dylan3,Joiner Evan F.4,Wilson Khadija3,Janssen Kevin3,Lee Pearl5,March Michael E.1,Nair Divya1,Sherr Elliott6ORCID,Fregeau Brieana6,Wierenga Klaas J.7,Wadley Alexandrea7,Mancini Grazia M. S.8,Powell-Hamilton Nina9,van de Kamp Jiddeke10,Grebe Theresa11,Dean John12ORCID,Ross Alison12,Crawford Heather P.13,Powis Zoe14,Cho Megan T.15,Willing Marcia C.16,Manwaring Linda16,Schot Rachel8,Nava Caroline1718,Afenjar Alexandra19,Lessel Davor2021ORCID,Wagner Matias222324,Klopstock Thomas252627ORCID,Winkelmann Juliane22242728,Catarino Claudia B.25,Retterer Kyle15,Schuette Jane L.29,Innis Jeffrey W.29,Pizzino Amy3031,Lüttgen Sabine32,Denecke Jonas32,Strom Tim M.2224,Monaghan Kristin G.15,Yuan Zuo-Fei3,Dubbs Holly3031,Bend Renee33,Lee Jennifer A.33,Lyons Michael J.33,Hoefele Julia24,Günthner Roman3435,Reutter Heiko36,Keren Boris18,Radtke Kelly37,Sherbini Omar3031,Mrokse Cameron37,Helbig Katherine L.37,Odent Sylvie38,Cogne Benjamin3940,Mercier Sandra3940,Bezieau Stephane3940,Besnard Thomas3940,Kury Sebastien3940ORCID,Redon Richard40,Reinson Karit4142,Wojcik Monica H.4344,Õunap Katrin4142,Ilves Pilvi45,Innes A. Micheil46,Kernohan Kristin D.4748,Costain Gregory49,Meyn M. Stephen4950,Chitayat David4951,Zackai Elaine52,Lehman Anna53,Kitson Hilary54,Martin Martin G.5556,Martinez-Agosto Julian A.5758,Nelson Stan F.5759,Palmer Christina G. S.5760,Papp Jeanette C.57,Parker Neil H.61,Sinsheimer Janet S.62,Vilain Eric63,Wan Jijun57,Yoon Amanda J.57,Zheng Allison57,Brimble Elise64,Ferrero Giovanni Battista65,Radio Francesca Clementina66,Carli Diana65,Barresi Sabina66,Brusco Alfredo67ORCID,Tartaglia Marco66,Thomas Jennifer Muncy68,Umana Luis69,Weiss Marjan M.10,Gotway Garrett69,Stuurman K. E.8,Thompson Michelle L.70,McWalter Kirsty15ORCID,Stumpel Constance T. R. M.71,Stevens Servi J. C.71ORCID,Stegmann Alexander P. A.71,Tveten Kristian72,Vøllo Arve73,Prescott Trine72,Fagerberg Christina74,Laulund Lone Walentin75,Larsen Martin J.74,Byler Melissa76,Lebel Robert Roger76,Hurst Anna C.77,Dean Joy77,Schrier Vergano Samantha A.78,Norman Jennifer79,Mercimek-Andrews Saadet49,Neira Juanita80,Van Allen Margot I.5381,Longo Nicola82,Sellars Elizabeth83,Louie Raymond J.33,Cathey Sara S.33,Brokamp Elly84,Heron Delphine18,Snyder Molly85,Vanderver Adeline3031,Simon Celeste4,de la Cruz Xavier8687,Padilla Natália86,Crump J. Gage2ORCID,Chung Wendy88,Garcia Benjamin23,Hakonarson Hakon H.1ORCID,Bhoj Elizabeth J.1ORCID, , , ,

Affiliation:

1. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

2. Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, CA 90033, USA.

3. Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

4. Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

5. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

6. Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.

7. Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL 32224, USA.

8. Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.

9. Department of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE 19810, USA.

10. Department of Clinical Genetics, VU Medical Center, Amsterdam, Netherlands.

11. Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA.

12. Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, Scotland, UK.

13. Clinical and Metabolic Genetics, Cook Children’s Medical Center, Fort Worth, TX 76104, USA.

14. Department of Emerging Genetic Medicine, Ambry Genetics, Aliso Viejo, CA 92656, USA.

15. GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.

16. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.

17. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France.

18. AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013 Paris, France.

19. Service de génétique, CRMR des malformations et maladies congénitales du cervelet et CRMR déficience intellectuelle, hôpital Trousseau, AP-HP, France.

20. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

21. Undiagnosed Disease Program at the University Medical Center Hamburg-Eppendorf (UDP-UKE), Martinistrasse 52, 20246 Hamburg, Germany.

22. Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

23. Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.

24. Institut für Humangenetik, Technische Universität München, Munich, Germany.

25. Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians University, Ziemssenstr. 1a, 80336 Munich, Germany.

26. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

27. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.

28. Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

29. Division of Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.

30. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

31. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA.

32. Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany.

33. Greenwood Genetic Center, Greenwood, SC 29646, USA.

34. Department of Nephrology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.

35. Institute of Human Genetics, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.

36. Department of Neonatology and Pediatric Intensive Care, Children’s Hospital, University Hospital Bonn & Institute of Human Genetics, University Hospital Bonn, Bonn, Germany.

37. Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.

38. CHU Rennes, Service de Génétique Clinique, CNRS UMR6290, University Rennes1, Rennes, France.

39. CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France.

40. INSERM, CNRS, UNIV Nantes, CHU Nantes, l’institut du thorax, 44007 Nantes, France.

41. Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.

42. Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

43. Division of Genetics and Genomics and Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

44. Broad Institute, Cambridge, MA 02142, USA.

45. Radiology Department of Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

46. Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

47. Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H8L1, Canada.

48. Newborn Screening Ontario (NSO), Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

49. Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.

50. The Center for Human Genomics and Precision Medicine, School of Medicine and Public Health, University of Wisconsin – Madison, Madison, Wisconsin 53705, USA.

51. The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada.

52. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

53. Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

54. Department of Pediatrics, University of British Columbia, Vancouver, Canada.

55. Division of Gastroenterology and Nutrition, Department of Pediatrics, Mattel Children’s Hospital, Los Angeles, CA 90095, USA.

56. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

57. Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

58. Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

59. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

60. Institute for Society and Genetics, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

61. David Geffen School of Medicine, Los Angeles, CA 90095, USA.

62. Institute for Society and Genetics, Departments of Human Genetics, Biomathematics, and Biostatistics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

63. Center for Genetic Medicine Research, Children’s National Medical Center, Washington, DC 20010, USA.

64. Department of Neurology and Neurological Sciences, Stanford Medicine, Stanford, CA 94305, USA.

65. Department of Public Health and Pediatrics, University of Torino, Turin, Italy.

66. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

67. Department of Medical Sciences, University of Torino, Turin, Italy.

68. Pediatrics and Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA.

69. Genetics and Metabolism, UT Southwestern Medical Center, Dallas, TX 75390, USA.

70. HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.

71. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands.

72. Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.

73. Department of Pediatrics, Hospital of Østfold, 1714 Grålum, Norway.

74. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

75. H.C. Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark.

76. SUNY Upstate Medical University, Syracuse, NY 13210, USA.

77. University of Alabama at Birmingham, Birmingham, AL 35294, USA.

78. Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk VA 23507, USA.

79. INTEGRIS Pediatric Neurology, Oklahoma City, OK 73112, USA.

80. Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

81. Medical Genetics Programs, Provincial Health Shared Services BC and Vancouver Island Health Shared Services BC, Canada.

82. Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA.

83. University of Arkansas for Medical Sciences, Little Rock, AR 72701, USA.

84. Vanderbilt University, Nashville, TN 37203, USA.

85. Child Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

86. Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

87. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

88. Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

Abstract

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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