Question: Which syndromes are associated with mutations in the EZH2 gene?

Context:
Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML)
We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH result
 Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure.
Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome
Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.
EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined
Weaver syndrome and EZH2 mutations
In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome
The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. 
Mutations in EZH2 cause Weaver syndrome
These data show that mutations in EZH2 cause Weaver syndrome
The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies
EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.
Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of EZH2 have been identified in patients with certain subtypes of non-Hodgkin lymphoma (NHL)
The EZH2 gene was previously reported to be located on chromosome 21q22 and was proposed as a candidate gene for some characteristics of the Down syndrome phenotype
Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN).
EZH2 is frequently overexpressed and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival.
In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome.
Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively.
Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.
Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.
The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes.
We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or EZH2 abnormalities.
Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). 
Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features. 
Recently, the advent of next generation sequencing (NGS) techniques has helped identify somatic gene mutations in 75-80% of MDS, that cluster mainly in four functional groups, i.e. cytokine signaling (RAS genes), DNA methylation, (TET2, IDH1/2, DNMT3a genes) histone modifications (ASXL1 and EZH2 genes), and spliceosome (SF3B1 and SRSF2 genes) along with mutations of RUNX1 and TP 53 genes.
Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains.
EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival.
Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes.
EZH2 is frequently overexpressed and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival.
Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap.
The deletion involved multiple genes, including two tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with MDS/AML.
Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features.

Answer: EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. These data show that mutations in EZH2 cause Weaver syndrome. The EZH2 gene is a homolog of the Drosophila Polycomb group (PcG) gene enhancer of zest, a crucial regulator of homeotic gene expression.
Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of EZH2 have been identified in patients with certain subtypes of non-Hodgkin lymphoma (NHL). The EZH2 gene is involved in the pathogenesis of 7q35-q36 aberrations in myeloid leukaemia.
Exact answer: myelodysplastic syndrome (MDS)
Acquired aplastic anemia (AA)
Weaver syndrome
non-Hodgkin lymphoma (NHL)
myeloid leukaemia