Coupling deep phenotypic quantification with next-generation phenotyping for 192 individuals with germline histonopathies
Human Genetics and Genomics Advances, vol. 6, pp. 100440
Abstract
Mendelian histonopathies are rare neurodevelopmental disorders (NDDs) caused by germline variants in histone-encoding genes. Here, we perform a more expansive pan-histonopathy interrogation than previously possible. We analyze data from 192 individuals affected by histonopathies. This analysis includes representation of the 185 published individuals with HIST1H1E syndrome, Bryant-Li-Bhoj syndrome, and Tessadori-Bicknell-van Haaften NDD; as well as from seven unpublished individuals, five of whom harbor variants in genes not previously associated with disease (HIST1H2AL/H2AC16, H2AFZ/H2AZ1, HIST1H3D/H3C4, and HIST3H3/H3-4). By intersecting clinician-reported phenotypic data with next-generation phenotyping of published 2D facial photographs (n = 98), we sought to address the lack of established craniofacial gestalts or characteristic phenotypic patterns for this community. While these analyses may suggest a histone core versus linker protein basis of delineation, they more strikingly highlight data gaps that confound the identification of phenotypic patterns at this time. Based on this, we developed an updated standardized clinical survey, which allowed us to identify the second known individual with a germline histonopathy and a cancer diagnosis. Notably, the community-wide cancer incidence is currently 1%, which falls below the recommended 5% cut off for routine surveillance. Ultimately, this work highlights the ways in which histonopathy-associated phenotypes change throughout the lifespan, necessitating longitudinal re-evaluation; that every identified individual shapes our understanding of these syndromes in a way that improves care for this community; and the value of ongoing translational work to address the outstanding question of cancer predisposition for individuals living with germline histonopathies.
Authors 28
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia
Affiliation as printed
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Director of Research Engagement, The TBCK Foundation, Pittsburgh, PA, USA
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States; Director of Research Engagement, The TBCK Foundation
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University of Bonn · University Hospital Bonn · Institut für Medizinische Biometrie, Informatik und Epidemiologie
Affiliation as printed
Institute for Genome Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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University of Bonn · University Hospital Bonn
Affiliation as printed
Institute for Genome Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia
Affiliation as printed
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia
Affiliation as printed
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia
Affiliation as printed
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia
Affiliation as printed
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Affiliation as printed
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Centre National de la Recherche Scientifique · Inserm · Centre Hospitalier Universitaire de Nantes · Institut du Thorax
Affiliation as printed
CHU de Nantes, Service de Génétique Médicale, Nantes, France; L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
CHU de Nantes, Service de Génétique Médicale, Nantes, France; L'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
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Centre National de la Recherche Scientifique · Inserm · Centre Hospitalier Universitaire de Nantes · Institut du Thorax
Affiliation as printed
CHU de Nantes, Service de Génétique Médicale, Nantes, France; L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
CHU de Nantes, Service de Génétique Médicale, Nantes, France; L'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
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Saskia Koene Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Leiden, the Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Yvonne Hilhorst‐Hofstee Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Leiden, the Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
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Affiliation as printed
Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
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Hospital La Paz Institute for Health Research
Affiliation as printed
INGEMM-IdiPaz, Institute of Medical and Molecular Genetics, Madrid, Spain
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Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
INGEMM-IdiPaz, Institute of Medical and Molecular Genetics, Madrid, Spain; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
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Hospital Infantil de México Federico Gómez
Affiliation as printed
Medical Genetics Department, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
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The University of Melbourne · Victorian Clinical Genetics Services · Murdoch Children's Research Institute
Affiliation as printed
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Pediatrics, University of Melbourne, Parkville, VIC, Australia
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia
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The University of Melbourne · Victorian Clinical Genetics Services · Murdoch Children's Research Institute
Affiliation as printed
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Pediatrics, University of Melbourne, Parkville, VIC, Australia
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Children's Hospital of Philadelphia
Affiliation as printed
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Elizabeth J. K. Bhoj corresponding
Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: bhoje@chop.edu
University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States. Electronic address: bhoje@chop.edu
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