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

Tessadori, Federico; Duran, Karen; Knapp, Karen; Fellner, M.; Smithson, Sarah; Beleza-Meireles, Ana; Elting, Mariet W.; Waisfisz, Quinten; O’Donnell-Luria, Anne; Nowak, C.; Douglas, Jessica; Ronan, Anne; Brunet, Theresa; Kotzaeridou, Urania; Svihovec, Shayna; Saenz, Margarita; Thiffault, Isabelle; Viso, Florencia Del; Devine, Patrick; Rego, Shannon; Tenney, Jessica; Haeringen, Arie van; Ruivenkamp, Claudia; Koene, Saskia; Robertson, Stephen; Deshpande, Charulata; Pfundt, Rolph; Verbeek, Nienke E.; Kamp, Jiddeke M. van de; Weiss, Janneke M M; Ruiz, Anna; Gabau, Elisabeth; Banne, Ehud; Pepler, Alexander; Laurent, Sacha; Guipponi, Michel; Bijlsma, Emilia K.; Bruel, Ange‐Line; Sorlin, Arthur; Willis, Mary; Powis, Zöe; Smol, Thomas; Vincent‐Delorme, Catherine; Baralle, Diana; Colin, Estelle; Revençu, Nicole; Calpena, Eduardo; Wilkie, Andrew; Chopra, Maya; Cormier‐Daire, Valérie; Keren, Boris; Afenjar, Alexandra; Niceta, Marcello; Terracciano, Alessandra; Specchio, Nicola; Tartaglia, Marco; Rio, Marlène; Barcia, Giulia; Rondeau, Sophie; Colson, Cindy; Bakkers, Jeroen; Mace, Peter D.; Bicknell, Louise S.; Haaften, Gijs van

doi:10.1016/j.ajhg.2022.02.003

Cited by 19 publications

(26 citation statements)

References 30 publications

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“…(B) Missense mutation sites (purple) located in the N-terminal tail and globular domain of H3.3, and a single nonsense mutation (red) located within an alternative H3F3B gene transcript 23–25. (C) Missense mutation sites (purple) located in the globular domain and C-terminal tail of H4 48 53 54. Spheres represent individual patients, with recurrent mutations stacked vertically.…”

Section: Mutations In Histone H1mentioning

confidence: 99%

“…Recently, we reported mutations in 6 of the 14 canonical histone H4 genes in individuals with a neurodevelopmental disorder (MIM 619758, 619759, 619950, 619951) 48 53 54. All mutations are de novo (or gonadal mosaic) and missense, and cluster into two main regions within the three-dimensional structure of H4, one around α-helix 1 and the second towards the C-terminal region of H4 (figure 3).…”

Section: Mutations In H4mentioning

confidence: 99%

“…The genes identified thus far cover both canonical and variant forms of different histones and replication-dependent and replication-independent, and in combination with the variety of histone-related functions, makes it difficult to conceive that there is a single molecular mechanism of pathogenesis. Combined with the clinical spectrum, even among individuals harbouring the same de novo variant, such as Arg45Cys in H4,53 this suggests there are different mechanisms and additional genetic or environmental influences shaping the final phenotypes observed.…”

Section: Histones In Brain Developmentmentioning

confidence: 99%

“…While several H3 variants do affect PTM sites, the majority of H3 and H4 variants are located within the core globular domain of each histone (figure 3). Modelling suggests that these residues are important for intranucleosome stability or histone-chaperone interactions 23 25 53. Thus, rather than simply alterations to PTM sites impacting gene expression, the disease mechanism is more nuanced and must involve disruption of nucleosome dynamics on chromatin, impacting potential multiple processes including transcription and DNA replication.…”

Section: Histones In Brain Developmentmentioning

confidence: 99%

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Histones: coming of age in Mendelian genetic disorders

et al. 2023

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Histones hold significant interest in development and genetic disorders due to their critical roles in chromatin dynamics, influencing gene expression and genome integrity. These roles are linked to alterations of post-translational marks, which are generally concentrated in the histone tails. The machinery modifying or interpreting these marks, known as chromatin writers, erasers or readers, have been associated with many Mendelian disorders; however, it has been only recently that the histone proteins themselves have been directly implicated in Mendelian conditions. High throughput sequencing has recently identified mutations in genes encoding histone H1, H3 and H4, all causing neurodevelopmental disorders with clinical variability. Notably, many of the mutations lie outside of recognised post-translational modification-associated residues, suggesting disrupting the core functions of histones is a primary molecular mechanism underpinning these neurodevelopmental phenotypes. In this review, we describe the clinical and genetic features of histone-related disorders, focusing on the unique aspects associated with each histone gene family, while noting the commonalities which provide insight into the required roles for histone fidelity in brain development and functioning.

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Section: Mutations In Histone H1mentioning

confidence: 99%

Section: Mutations In H4mentioning

confidence: 99%

Section: Histones In Brain Developmentmentioning

confidence: 99%

Section: Histones In Brain Developmentmentioning

confidence: 99%

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Histones: coming of age in Mendelian genetic disorders

et al. 2023

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“…Specifically, we observed that the two most common features of MDEMs are intellectual disability and growth abnormalities. In addition, disease-causing variants in genes encoding other components of histone-modifying complexes without these specific domains, such as scaffolding proteins (Imagawa et al 2017 ; Machol et al 2019 ) and genes encoding histones themselves (Najmabadi et al 2011 ; Tatton-Brown et al 2017 ; Bryant et al 2020 ; Tessadori et al 2022 ), have been described more recently. These disorders, encompassed by the broader term “Chromatinopathies,” have overlapping phenotypes with MDEMs, including intellectual disability and growth dysregulation (defined as growth retardation or overgrowth), among others, supporting the notion that histone modification plays a key role.…”

Section: Introductionmentioning

confidence: 99%

Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?

et al. 2023

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The multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins provides comprehensive medical care for individuals with rare disorders that involve disrupted epigenetics. Initially centered on classical imprinting disorders, the focus shifted to the rapidly emerging group of genetic disorders resulting from pathogenic germline variants in epigenetic machinery genes. These are collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), or more broadly, Chromatinopathies. In five years, 741 clinic visits have been completed for 432 individual patients, with 153 having confirmed epigenetic diagnoses. Of these, 115 individuals have one of 26 MDEMs with every single one exhibiting global developmental delay and/or intellectual disability. This supports prior observations that intellectual disability is the most common phenotypic feature of MDEMs. Additional common phenotypes in our clinic include growth abnormalities and neurodevelopmental issues, particularly hypotonia, attention-deficit/hyperactivity disorder (ADHD), and anxiety, with seizures and autism being less common. Overall, our patient population is representative of the broader group of MDEMs and includes mostly autosomal dominant disorders impacting writers more so than erasers, readers, and remodelers of chromatin marks. There is an increased representation of dual function components with a reader and an enzymatic domain. As expected, diagnoses were made mostly by sequencing but were aided in some cases by DNA methylation profiling. Our clinic has helped to facilitate the discovery of two new disorders, and our providers are actively developing and implementing novel therapeutic strategies for MDEMs. These data and our high follow-up rate of over 60% suggest that we are achieving our mission to diagnose, learn from, and provide optimal care for our patients with disrupted epigenetics.

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H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome

Borja

Borjas-Mendoza

Bivona

et al. 2023

American J of Med Genetics Pt A

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Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4‐year‐old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease‐causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4‐associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

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

Cited by 19 publications

References 30 publications

Histones: coming of age in Mendelian genetic disorders

Histones: coming of age in Mendelian genetic disorders

Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome

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