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

doi:10.1016/j.ajhg.2022.02.003

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

10 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	750-758
Number of pages	9
Journal	American Journal of Human Genetics
Volume	109
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2022.02.003
Publication status	Published - 07 Apr 2022

Keywords

Animals
Chromatin
DNA
Histones/metabolism
Humans
Syndrome
Zebrafish/genetics

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10.1016/j.ajhg.2022.02.003

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@article{028cefa2f1cb4dea8faf5779816f6a94,

title = "Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome",

abstract = "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.",

keywords = "Animals, Chromatin, DNA, Histones/metabolism, Humans, Syndrome, Zebrafish/genetics",

author = "Federico Tessadori and Karen Duran and Karen Knapp and Matthias Fellner and Sarah Smithson and {Beleza Meireles}, Ana and Elting, {Mariet W} and Quinten Waisfisz and Anne O'Donnell-Luria and Catherine Nowak and Jessica Douglas and Anne Ronan and Theresa Brunet and Urania Kotzaeridou and Shayna Svihovec and Saenz, {Margarita S} and Isabelle Thiffault and {Del Viso}, Florencia and Patrick Devine and Shannon Rego and Jessica Tenney and {van Haeringen}, Arie and Ruivenkamp, {Claudia A L} and Saskia Koene and Robertson, {Stephen P} and Charulata Deshpande and Rolph Pfundt and Nienke Verbeek and {van de Kamp}, {Jiddeke M} and Weiss, {Janneke M M} and Anna Ruiz and Elisabeth Gabau and Ehud Banne and Alexander Pepler and Armand Bottani and Sacha Laurent and Michel Guipponi and Emilia Bijlsma and Ange-Line Bruel and Arthur Sorlin and Mary Willis and Zoe Powis and Thomas Smol and Catherine Vincent-Delorme and Diana Baralle and Estelle Colin and Nicole Revencu and Eduardo Calpena and Wilkie, {Andrew O M} and Jeroen Bakkers",

year = "2022",

month = apr,

day = "7",

doi = "10.1016/j.ajhg.2022.02.003",

language = "English",

volume = "109",

pages = "750--758",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

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TY - JOUR

T1 - Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome

AU - Tessadori, Federico

AU - Duran, Karen

AU - Knapp, Karen

AU - Fellner, Matthias

AU - Smithson, Sarah

AU - Beleza Meireles, Ana

AU - Elting, Mariet W

AU - Waisfisz, Quinten

AU - O'Donnell-Luria, Anne

AU - Nowak, Catherine

AU - Douglas, Jessica

AU - Ronan, Anne

AU - Brunet, Theresa

AU - Kotzaeridou, Urania

AU - Svihovec, Shayna

AU - Saenz, Margarita S

AU - Thiffault, Isabelle

AU - Del Viso, Florencia

AU - Devine, Patrick

AU - Rego, Shannon

AU - Tenney, Jessica

AU - van Haeringen, Arie

AU - Ruivenkamp, Claudia A L

AU - Koene, Saskia

AU - Robertson, Stephen P

AU - Deshpande, Charulata

AU - Pfundt, Rolph

AU - Verbeek, Nienke

AU - van de Kamp, Jiddeke M

AU - Weiss, Janneke M M

AU - Ruiz, Anna

AU - Gabau, Elisabeth

AU - Banne, Ehud

AU - Pepler, Alexander

AU - Bottani, Armand

AU - Laurent, Sacha

AU - Guipponi, Michel

AU - Bijlsma, Emilia

AU - Bruel, Ange-Line

AU - Sorlin, Arthur

AU - Willis, Mary

AU - Powis, Zoe

AU - Smol, Thomas

AU - Vincent-Delorme, Catherine

AU - Baralle, Diana

AU - Colin, Estelle

AU - Revencu, Nicole

AU - Calpena, Eduardo

AU - Wilkie, Andrew O M

AU - Bakkers, Jeroen

PY - 2022/4/7

Y1 - 2022/4/7

N2 - 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.

AB - 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.

KW - Animals

KW - Chromatin

KW - DNA

KW - Histones/metabolism

KW - Humans

KW - Syndrome

KW - Zebrafish/genetics

U2 - 10.1016/j.ajhg.2022.02.003

DO - 10.1016/j.ajhg.2022.02.003

M3 - Article

C2 - 35202563

SN - 0002-9297

VL - 109

SP - 750

EP - 758

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

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

Abstract

Keywords

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