Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome

• DOI: 10.1016/j.ajhg.2022.02.003
• Publication Date: 2022-02-23T04:11:42Z
• Authors: Federico Tessadori; Karen Duran; Karen Knapp; Matthias Fellner; Sarah Smithson; Ana Beleza Meireles; Mariet W. Elting; Quinten Waisfisz; Anne O’Donnell-Luria; Catherine Nowak; Jessica Douglas; Anne Ronan; Theresa Brunet; Urania Kotzaeridou; Shayna Svihovec; Margarita S. Saenz; Isabelle Thiffault; Florencia Del Viso; Patrick Devine; Shannon Rego; Jessica Tenney; Arie van Haeringen; Claudia A.L. Ruiv...; Saskia Koene; Stephen P. Robertson; Charulata Deshpande; Rolph Pfundt; Nienke Verbeek; Jiddeke M. van de...; Janneke M.M. Weiss; Anna Ruiz; Elisabeth Gabau; Ehud Banne; Alexander Pepler; Armand Bottani; Sacha Laurent; Michel Guipponi; Emilia Bijlsma; Ange-Line Bruel; Arthur Sorlin; Mary Willis; Zoe Powis; Thomas Smol; Catherine Vincent...; Diana Baralle; Estelle Colin; Nicole Revencu; Eduardo Calpena; Andrew O.M. Wilkie; Maya Chopra; Valerie Cormier-D...; Boris Keren; Alexandra Afenjar; Marcello Niceta; Alessandra Terrac...; Nicola Specchio; Marco Tartaglia; Marlene Rio; Giulia Barcia; Sophie Rondeau; Cindy Colson; Jeroen Bakkers; Peter D. Mace; Louise S. Bicknell; Gijs van Haaften
• Keywords: 0301 basic medicine; 570; Histones/metabolism; Intellectual disability; 610; Zebrafish/genetics; Histones; histone H4, intellectual disability, microcephaly, neurodevelopmental disorder, nucleosome, zebrafish; 03 medical and health sciences; histone H4; Neurodevelopmental disorder; Report; Animals; Humans; microcephaly; Zebrafish; 0303 health sciences; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Histone H4; nucleosome; DNA; Syndrome; zebrafish; neurodevelopmental disorder; Chromatin; [SDV] Life Sciences [q-bio]; Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences; intellectual disability; Nucleosome; Microcephaly

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.