Mutations in EZH2 Cause Weaver Syndrome

Gibson, William T.; Hood, Rebecca L.; Zhan, Shing Hei; Bulman, Dennis E.; Fejes, Anthony P.; Moore, Richard A.; Mungall, Andrew J.; Eydoux, Patrice; Babul‐Hirji, Riyana; An, Jianghong; Marra, Marco A.; Chitayat, David; Boycott, Kym M.; Weaver, David D.; Jones, Steven J.M.

doi:10.1016/j.ajhg.2011.11.018

Cited by 254 publications

(186 citation statements)

References 35 publications

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“…We find that beyond a dysmorphic skull, loss of Ezh2 in mesenchymal cells also causes clinodactyly. Similar skull and hand abnormalities are seen in patients with Weaver syndrome that have hypomorphic germline mutations in EZH2 (65)(66)(67). Furthermore, limb and spine abnormalities we observe in mice with a mesenchymal deletion of Ezh2 reflect growth plate abnormalities that are reminiscent of human osteochondrodysplasias.…”

Section: Discussionsupporting

confidence: 65%

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

Dudakovic

Camilleri

et al. 2015

Journal of Biological Chemistry

149

179

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Background: Osteogenic differentiation is initiated by transcriptional and post-transcriptional epigenetic mechanisms. Results: Inhibition of H3K27 methyltransferase EZH2 enhances osteogenic commitment of human mesenchymal progenitors, and its depletion in mouse mesenchymal cells causes multiple skeletal abnormalities. Conclusion: EZH2 is required for skeletal patterning and bone formation. Significance: EZH2-dependent epigenetic mechanisms control osteogenesis both in vitro and in vivo.

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Section: Discussionsupporting

confidence: 65%

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

Dudakovic

Camilleri

et al. 2015

Journal of Biological Chemistry

149

179

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“…In the last decade, the field has witnessed an explosion in the discovery of mutations in the various components of the epigenetic machinery (Kleefstra et al 2006;Ng et al 2010;Gibson et al 2012); mutations in many of these components have now been linked to a number of well-known causes of intellectual disability. Intellectual disability is generally defined as deficits of intellectual function and adaptive behavior that occur during the developmental period (see, e.g., http://aaidd.org).…”

mentioning

confidence: 99%

The Mendelian disorders of the epigenetic machinery

2015

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The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a common phenotype; however, this is often seen in association with other more specific features in respective disorders. The specificity of some of the clinical features raises the question whether specific cell types are particularly sensitive to the loss of these factors. Most of these disorders demonstrate dosage sensitivity as loss of a single allele appears to be sufficient to cause the observed phenotypes. Although the pathogenic sequence is unknown for most of these disorders, there are several examples where disrupted expression of downstream target genes accounts for a substantial portion of the phenotype; hence, it may be useful to systematically map such disease-relevant target genes. Finally, two of these disorders (Rubinstein-Taybi and Kabuki syndromes) have shown post-natal rescue of markers of the neurological dysfunction with drugs that lead to histone deacetylase inhibition, indicating that some of these disorders may be treatable causes of intellectual disability.

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“…Weaver Tumor frequency of perhaps 4% including neuroblastoma, acute lymphoblastic leukemia, ovarian endodermal sinus tumor, sacrococcygeal teratoma, and lymphoma Basel-Vanagaite, 2010;Gibson et al, 2012;Tatton-Brown and Rahman, 2013;. No specific protocol for cancer surveillance has yet been validated.…”

Section: Sotosmentioning

confidence: 99%

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

et al. 2018

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The overgrowth syndromes are important to diagnose, not just for accurate genetic counseling, but also for knowledge surrounding cancer surveillance and prognosis. There has been a recent expansion in the number of genes associated with a mendelian overgrowth phenotype, so this review updates previous classifications of overgrowth syndromes. We also describe a clinical and molecular approach to the investigation of individuals presenting with overgrowth. This review aims to assist the clinical diagnosis of generalized overgrowth syndromes by outlining the salient features of well-known overgrowth syndromes alongside the many syndromes that have been discovered and classified more recently. We provide key clinical “handles” to aid clinical diagnosis and a list of genes to aid with panel design when using next generation sequencing, which we believe is frequently needed due to the overlapping phenotypic features seen between overgrowth syndromes.

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Mutations in EZH2 Cause Weaver Syndrome

Cited by 254 publications

References 35 publications

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

The Mendelian disorders of the epigenetic machinery

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

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