Coupling deep phenotypic quantification with next-generation phenotyping for 192 individuals with germline histonopathies

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with HIST1H1E syndrome, Bryant-Li-Bhoj syndrome, and Tessadori-Bicknell-van Haaften NDD; as well as from seven unpublished individuals, five of whom harbor variants in genes not previously associated with disease (HIST1H2AL/H2AC16, H2AFZ/H2AZ1, HIST1H3D/H3C4, and HIST3H3/H3-4).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.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-04-15
DOI
https://doi.org/10.1016/j.xhgg.2025.100440
Citations
2
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
3.63
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article

Coupling deep phenotypic quantification with next-generation phenotyping for 192 individuals with germline histonopathies

Emily L. Durham, Margarita Cano, Emily E. Lubin, Jingmei Li et al.
2 citations
Human Genetics and Genomics Advances
Genomics and Rare Diseases
3.63
article

Coupling deep phenotypic quantification with next-generation phenotyping for 192 individuals with germline histonopathies

Emily L. Durham, Margarita Cano, Emily E. Lubin, Jingmei Li, Hannah Klinkhammer, Elizabeth M. Gonzalez, Ashley J. Melendez-Perez, Rafał Płoski, Saskia Koene, Tahsin Stefan Barakat, Tania Barragán-Arévalo, Małgorzata Rydzanicz, Tiong Yang Tan, Rajesh Angireddy, Tomoki Nomakuchi, Yvonne Hilhorst‐Hofstee, Lyndon Gallacher, María Palomares‐Bralo, Annabel K. Sangree, Suzanne P. MacFarland, Rebecca C. Ahrens‐Nicklas, Kelly James Clark, Dana E. Layo-Carris, Elizabeth Bhoj, Erin Weiss, Sarina Smith, Benjamin Cogné, Xiao Min Wang, Sandra Mercier
article en
2 citations

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.

Human Genetics and Genomics AdvancesVol. 6(3)
Centre National de la Recherche Scientifique (FR), Children's Hospital of Philadelphia (US), University of Bonn (DE), Inserm (FR), Medical University of Warsaw (PL), University Hospital Bonn (DE), Leiden University Medical Center (NL), Erasmus MC (NL), Hospital Infantil de México Federico Gómez (MX), Hospital La Paz Institute for Health Research (ES), Victorian Clinical Genetics Services (AU), Centro de Investigación Biomédica en Red (ES), Institut du Thorax (FR), Instituto de Investigación de Enfermedades Raras (ES)
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Genomics and Rare Diseases
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