HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Deepika D'Cunha Burkardt¹, Anna Zachariou², Chey Loveday², Clare L Allen³, David J Amor⁴, Anna Ardissone⁵, Siddharth Banka^{6

7}, Alexia Bourgois⁸, Christine Coubes⁹, Cheryl Cytrynbaum¹⁰, Laurence Faivre¹¹, Gerard Marion¹², Rachel Horton¹³, Dieter Kotzot¹⁴, Guillermo Lay-Son¹⁵, Melissa Lees¹⁶, Karen Low¹⁷, Ho-Ming Luk¹⁸, Paul Mark¹⁹, Allyn McConkie-Rosell²⁰, Marie McDonald²⁰, John Pappas²¹, Christophe Phillipe²², Deborah Shears²³, Brian Skotko²⁴, Fiona Stewart²⁵, Helen Stewart²⁶, I Karen Temple²⁷, Frederic T Mau-Them²⁸, Ricardo A Verdugo²⁹, Rosanna Weksberg¹⁰, Yuri A Zarate³⁰, John M Graham³¹, Katrina Tatton-Brown^{2

32

33}

Affiliations

¹ Center for Human Genetics,University Hospitals Rainbow Babies and Children, Department of genetics, Case Western Reserve University, Cleveland, Ohio.
² Institute of Cancer Research, London, UK.
³ Lowerbank Dental Practice, Leyland, UK.
⁴ Department of Paediatrics, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria, Australia.
⁵ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Lombardia, Italy.
⁶ Faculty of Biology, Medicine and Health, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
⁷ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
⁸ CHU Côte de Nacre, Service de Génétique, Caen, France.
⁹ Hôpital Arnaud de Villeneuve Montpellier, Montpellier, France.
¹⁰ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Genetics Center, Hôpital d'Enfants, Dijon, France.
¹² Service de Génétique, Centre Hospitalier Universitaire de Caen Normandie, Caen, France.
¹³ University Hospital Southampton NHS Foundation Trust, Southampton, UK.
¹⁴ Division of Clinical Genetics, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
¹⁵ División de Pediatría, Pontificia Universidad Católica de Chile, Santiago, Chile.
¹⁶ Clinical Genetics Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
¹⁷ Clinical Genetics, St Michaels Hospital, University Hospitals Bristol, Bristol, UK.
¹⁸ Department of Health, Clinical Genetic Service, Hong Kong, Hong Kong.
¹⁹ Spectrum Health Division of Medical Genetics, Grand Rapids, Michigan.
²⁰ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Genetics, Durham, North Carolina.
²¹ Human Genetics Program, University School of Medicine, New York, New York, USA.
²² UF Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon Bourgogne, INSERM UMR1231 GAD, Dijon, France.
²³ Clinical Genetics, Churchill Hospital, Oxford, UK.
²⁴ Division of Medical Genetics and Genomics, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
²⁵ Medical Genetics, Belfast City Hospital, Belfast, UK.
²⁶ Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford, UK.
²⁷ Faculty of Medicine, Wessex Clinical Genetics Service, University Hospital Southampton, University of Southampton, Southampton, UK.
²⁸ UF D'innovation en Génétique Moléculaire, Plateau Technique de Biologie, Centre Hospitalier Universitaire de Dijon, FHU TRANSLAD, Dijon, France.
²⁹ Programa de Genética Humans, ICBM, Santiago, Chile.
³⁰ Section of Genetics and Metabolism, Arkansas Children's Hospital, Little Rock, Arkansas.
³¹ Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, California.
³² South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
³³ St George's University of London, London, UK.

PMID: 31400068
DOI: 10.1002/ajmg.a.61321

HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Deepika D'Cunha Burkardt et al. Am J Med Genet A. 2019 Oct.

. 2019 Oct;179(10):2049-2055.

doi: 10.1002/ajmg.a.61321. Epub 2019 Aug 9.

Authors

Affiliations

¹ Center for Human Genetics,University Hospitals Rainbow Babies and Children, Department of genetics, Case Western Reserve University, Cleveland, Ohio.
² Institute of Cancer Research, London, UK.
³ Lowerbank Dental Practice, Leyland, UK.
⁴ Department of Paediatrics, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria, Australia.
⁵ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Lombardia, Italy.
⁶ Faculty of Biology, Medicine and Health, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
⁷ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
⁸ CHU Côte de Nacre, Service de Génétique, Caen, France.
⁹ Hôpital Arnaud de Villeneuve Montpellier, Montpellier, France.
¹⁰ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Genetics Center, Hôpital d'Enfants, Dijon, France.
¹² Service de Génétique, Centre Hospitalier Universitaire de Caen Normandie, Caen, France.
¹³ University Hospital Southampton NHS Foundation Trust, Southampton, UK.
¹⁴ Division of Clinical Genetics, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
¹⁵ División de Pediatría, Pontificia Universidad Católica de Chile, Santiago, Chile.
¹⁶ Clinical Genetics Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
¹⁷ Clinical Genetics, St Michaels Hospital, University Hospitals Bristol, Bristol, UK.
¹⁸ Department of Health, Clinical Genetic Service, Hong Kong, Hong Kong.
¹⁹ Spectrum Health Division of Medical Genetics, Grand Rapids, Michigan.
²⁰ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Genetics, Durham, North Carolina.
²¹ Human Genetics Program, University School of Medicine, New York, New York, USA.
²² UF Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon Bourgogne, INSERM UMR1231 GAD, Dijon, France.
²³ Clinical Genetics, Churchill Hospital, Oxford, UK.
²⁴ Division of Medical Genetics and Genomics, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
²⁵ Medical Genetics, Belfast City Hospital, Belfast, UK.
²⁶ Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford, UK.
²⁷ Faculty of Medicine, Wessex Clinical Genetics Service, University Hospital Southampton, University of Southampton, Southampton, UK.
²⁸ UF D'innovation en Génétique Moléculaire, Plateau Technique de Biologie, Centre Hospitalier Universitaire de Dijon, FHU TRANSLAD, Dijon, France.
²⁹ Programa de Genética Humans, ICBM, Santiago, Chile.
³⁰ Section of Genetics and Metabolism, Arkansas Children's Hospital, Little Rock, Arkansas.
³¹ Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, California.
³² South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
³³ St George's University of London, London, UK.

PMID: 31400068
DOI: 10.1002/ajmg.a.61321

Abstract

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.

Keywords: HIST1H1E; Rahman syndrome; epigenetic regulator gene; intellectual disability.

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References

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HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Affiliations

HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

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