Novel <i>SUZ12</i> mutations in Weaver‐like syndrome

Imagawa, Eri; Albuquerque, Edoarda V A; Isidor, Bertrand; Mitsuhashi, Satomi; Mizuguchi, Takeshi; Miyatake, Satoko; Takata, Atsushi; Miyake, Noriko; Boguszewski, Margaret Cristina da Silva; Boguszewski, César Luiz; Lerário, Antônio Marcondes; Funari, Mariana A.; Jorge, Alexander A L; Matsumoto, Naomichi

doi:10.1111/cge.13415

Cited by 44 publications

(51 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 48 , 49 , 50 Not surprisingly, individuals with EZH2 , EED , and SUZ12 pathogenic variants present with overlapping phenotypes, including generalized overgrowth, similar craniofacial features, advanced bone maturation, macrocephaly, and variable degrees of intellectual disability. 51 As there are few specific clinical features that distinguish each of these three disorders from each other, it is difficult in many of these individuals, for even the most astute clinician, to define specific genomic diagnosis in a particular case. Here we show that the pathogenic sequence variants in these genes that confer similar phenotypes also confer a common DNAm signature that represents the functional effect of PRC2 perturbation during development.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

Choufani

Gibson

Turinsky

et al. 2020

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2 , which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12 , which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2 , EED , and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

show abstract

Section: Discussionmentioning

confidence: 99%

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

Choufani

Gibson

Turinsky

et al. 2020

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

show abstract

“…For E(z) to have complete catalytic activity to generate the H3K27me3 mark, E(z) requires the presence of both Esc and Su(z)12 [20]. Interestingly, mutations in EZH2, EED and SU(z)12 have all been found in patients with Weaver syndrome, a rare congenital disorder characterized by intellectual disabilities, accelerated bone age and general overgrowth of the head and facial features [21][22][23]. In vitro assays demonstrate that several of the identified mutations in these core proteins reduce the histone methyltransferase ability of PRC2 [24,25].…”

Section: Polycomb Repressive Complexmentioning

confidence: 99%

The Dynamic Partnership of Polycomb and Trithorax in Brain Development and Diseases

Kuehner

Yao

2019

Epigenomes

View full text Add to dashboard Cite

Epigenetic mechanisms, including DNA and histone modifications, are pivotal for normal brain development and functions by modulating spatial and temporal gene expression. Dysregulation of the epigenetic machinery can serve as a causal role in numerous brain disorders. Proper mammalian brain development and functions depend on the precise expression of neuronal-specific genes, transcription factors and epigenetic modifications. Antagonistic polycomb and trithorax proteins form multimeric complexes and play important roles in these processes by epigenetically controlling gene repression or activation through various molecular mechanisms. Aberrant expression or disruption of either protein group can contribute to neurodegenerative diseases. This review focus on the current progress of Polycomb and Trithorax complexes in brain development and disease, and provides a future outlook of the field.

show abstract

“…All EZH2 mutations currently described to cause Weaver syndrome are either missense variants or truncating variants of the last exon ( Tatton-Brown et al 2018 ). Rare de novo mutations in EED were recently reported to cause Cohen–Gibson syndrome ( Cohen et al 2015 ; Cohen and Gibson 2016 ), whereas SUZ12 -related overgrowth (also referred to as Weaver-like syndrome) is caused by rare variants in its namesake gene ( Imagawa et al 2017 ; Imagawa et al 2018 ; Cyrus et al 2019 ). Similar to Weaver syndrome, reported mutations in EED and SUZ12 impair H3K27me3 formation ( Imagawa et al 2017 ), in line with the role these core components play in stabilizing PRC2 enzyme function.…”

Section: Regulators Of the H3k27 Transcriptional Switchmentioning

confidence: 99%

Reciprocal skeletal phenotypes of PRC2-related overgrowth and Rubinstein–Taybi syndromes: potential role of H3K27 modifications

Gamu

Gibson

2020

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

Within histone H3, lysine 27 (H3K27) is one of the residues that functions as a molecular switch, by virtue of being subject to mutually exclusive post-translational modifications that have reciprocal effects on gene expression. Whereas acetylation of H3K27 is associated with transcriptional activation, methylation at this residue causes transcriptional silencing; these two modifications are mutually exclusive. Establishment of these epigenetic marks is important in defining cellular identity and for maintaining normal cell function, as evidenced by rare genetic disorders of epigenetic writers involved in H3K27 post-translational modification. Polycomb repressive complex (PRC2)-related overgrowth and Rubinstein-Taybi syndrome (RSTS) are respectively associated with impaired H3K27 methylation and acetylation. Whereas these syndromes share commonalities like intellectual disability and susceptibility to cancers, they are generally divergent in their skeletal growth phenotypes, potentially through dysregulation of their opposing H3K27 writer functions. In this review, we discuss the requirement of H3K27 modifications for successful embryogenesis, highlighting data from relevant mouse knockout studies. Although such gene ablation studies are integral for defining fundamental biological roles of methyl-and acetyltransferase function in vivo, studies of partial loss-of-function models are likely to yield more meaningful translational insight into progression of PRC2-related overgrowth or RSTS. Thus, modeling of rare human PRC2-related overgrowth and RSTS variants in mice is needed to fully understand the causative role of aberrant H3K27 modification in the pathophysiology of these syndromes.

show abstract

Novel SUZ12 mutations in Weaver‐like syndrome

Cited by 44 publications

References 21 publications

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

The Dynamic Partnership of Polycomb and Trithorax in Brain Development and Diseases

Reciprocal skeletal phenotypes of PRC2-related overgrowth and Rubinstein–Taybi syndromes: potential role of H3K27 modifications

Contact Info

Product

Resources

About