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: Histone H4; Histone code; Histone Methylation; Histone octamer

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