Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome
Histone H4
Histone code
Histone Methylation
Histone octamer
DOI:
10.1016/j.ajhg.2022.02.003
Publication Date:
2022-02-23T04:11:42Z
AUTHORS (65)
ABSTRACT
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.
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