Alternative titles; symbols
HGNC Approved Gene Symbol: EZH2
SNOMEDCT: 63119004; ICD10CM: Q87.3;
Cytogenetic location: 7q36.1 Genomic coordinates (GRCh38) : 7:148,807,383-148,884,291 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.1 | Weaver syndrome | 277590 | Autosomal dominant | 3 |
The EZH2 gene encodes a histone methyltransferase that constitute the catalytic component of the polycomb repressive complex-2 (PRC2), which functions to initiate epigenetic silencing of genes involved in cell fate decisions. EZH2 specifically methylates nucleosomal histone H3 (see 602810) at lysine-27 (H3-K27) (summary by Cao et al., 2002 and Ernst et al., 2010).
To identify genes that map on human chromosome 21 that may contribute to the phenotype of Down syndrome, Chen et al. (1996) applied exon trapping to cosmid DNA from a chromosome 21-specific library. One of the potential exons that was cloned and partially characterized showed strong homology to the Drosophila 'enhancer of zeste' protein from amino acid 665 to amino acid 694. The Drosophila protein is a member of the Polycomb group, which maintains homeotic gene repression and is thought to control gene expression by regulating chromatin. Chen et al. (1996) cloned the full-length cDNA for this human homolog, termed EZH2.
Cardoso et al. (2000) reported the characteristics of all 20 exons of the EZH2 gene and the adjoining splice donor and splice acceptor sites and gave the size of the 19 introns. Transcription began near the beginning of exon 2.
Chen et al. (1996) mapped the human EZH2 cDNA within YACs between marker D21S65 and ERG (165080) on 21q22.2. However, Cardoso et al. (2000) later showed by FISH that the functional EZH2 gene maps to 7q35, not 21q22, and that the sequence isolated from the chromosome 21 cosmid corresponds to a pseudogene.
By FISH, Laible et al. (1999) mapped the mouse Ezh2 gene to chromosome 6.
Several lines of evidence suggested a critical role for the EZH2 protein during normal and perturbed development of the hematopoietic and central nervous systems. Indeed, the EZH2 protein has been shown to associate with the VAV1 protooncoprotein (164875) and with the XNP protein (300032), the product of a gene associated with mental retardation (Cardoso et al., 1998).
The nature of the EZH2 protein and its mapping to the critical region for malignant myeloid disorders led Cardoso et al. (2000) to propose that the EZH2 gene is involved in the pathogenesis of 7q35-q36 aberrations in myeloid leukemia (Dohner et al., 1998).
Varambally et al. (2002) demonstrated through gene expression profiling that EZH2 is overexpressed in hormone-refractory, metastatic prostate cancer (see 176807). Small interfering RNA (siRNA) duplexes targeted against EZH2 reduced the amounts of EZH2 protein present in prostate cells and also inhibited cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induced transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 mRNA and EZH2 protein were increased in metastatic prostate cancer. In addition, clinically localized prostate cancers that expressed higher concentrations of EZH2 showed a poorer prognosis. Thus, Varambally et al. (2002) concluded that dysregulated expression of EZH2 may be involved in the progression of prostate cancer as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
Cao et al. (2002) reported the purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex. Cao et al. (2002) demonstrated that the complex specifically methylates nucleosomal histone H3 (see 601128) at lysine-27 (H3-K27). Using chromatin immunoprecipitation assays, Cao et al. (2002) showed that H3-K27 methylation colocalizes with, and is dependent on, E(Z) binding at an 'Ultrabithorax' (Ubx) Polycomb response element, and that this methylation correlates with Ubx expression. Methylation on H3-K27 facilitates binding of Polycomb, a component of the Polycomb repressive complex 1 (PRC1 complex), to the histone H3 N-terminal tail. Thus, Cao et al. (2002) concluded that their studies established a link between histone methylation and Polycomb group-mediated gene silencing. The complex responsible for histone methyltransferase activity included EZH2, SUZ12 (606245), and EED (605984). EZH2 contains a SET domain, a signature motif for all known histone lysine methyltransferases except the H3-K79 methyltransferase DOT1, and is therefore likely to be the catalytic subunit.
Plath et al. (2003) demonstrated that transient recruitment of the EED-EZH2 complex to the inactive X chromosome occurs during initiation of X inactivation in both extraembryonic and embryonic cells and is accompanied by H3-K27 methylation. Recruitment of the complex and methylation on the inactive X depend on Xist (314670) RNA but are independent of its silencing function. Plath et al. (2003) concluded that taken together, their results suggest a role for EED-EZH2-mediated H3-K27 methylation during initiation of both imprinted and random X inactivation and demonstrate that H3-K27 methylation is not sufficient for silencing of the inactive X.
Cha et al. (2005) showed that AKT (164730) phosphorylates EZH2 at serine-21 and suppresses its methyltransferase activity by impeding EZH2 binding to histone H3, which results in a decrease of lysine-27 trimethylation and derepression of silenced genes. Cha et al. (2005) concluded that their results imply that AKT regulates the methylation activity, through phosphorylation of EZH2, which may contribute to oncogenesis.
Vire et al. (2006) showed that the silencing pathways of the polycomb group (PcG) and DNA methyltransferases systems are mechanically linked. They found that the PcG protein EZH2 interacts--within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)--with DNA methyltransferases DNMT1 (126375), DNMT3A (602769), and DNMT3B (602900) and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicated that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Furthermore, Vire et al. (2006) showed by bisulfite genomic sequencing that EZH2 is required for DNA methylation of EZH2-target promoters. Vire et al. (2006) concluded that their results suggest that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between 2 key epigenetic repression systems.
As indicated by the work of Kamminga et al. (2006), EZH2 is, like latexin (LXN; 609305), a stem cell regulator.
Varambally et al. (2008) demonstrated that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA 101 (MIRN101; see 612511). Analysis of human prostate tumors revealed that MIRN101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the 2 genomic loci encoding MIRN101 were somatically lost in 37.5% of clinically localized prostate cancer (see 176807) cells (6 of 16) and 66.7% of metastatic disease cells (22 of 33). Varambally et al. (2008) proposed that the genomic loss of MIRN101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.
Terranova et al. (2008) found that mouse Ezh2 and Rnf2 (608985) were independently required for genomic contraction and repression of imprinted genes during early embryonic development.
The gene silencing activity of the Polycomb repressive complex-2 (PRC2; see 601674) depends on its ability to trimethylate lys27 of histone 3 (H3K27) by the catalytic SET domain of the EZH2 subunit and at least 2 other subunits of the complex: SUZ12 (606245) and EED (605984). Margueron et al. (2009) showed that the carboxy-terminal domain of EED specifically binds to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in EED that prevent it from recognizing repressive trimethyl-lysine marks abolished the activation of PRC2 in vitro and, in Drosophila, reduced global methylation and disrupted development. Margueron et al. (2009) concluded that their findings suggested a model for the propagation of the H3K27 methyl-3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission of a histone modification from mother to daughter cells.
Chen et al. (2005) showed that increased EZH2 expression in normal human prostate epithelial cells suppressed DAB2IP (609205) gene expression. In contrast, knockdown of endogenous EZH2 levels in prostate cancer cells via siRNA increased DAB2IP expression. In prostate cancer, but not normal prostate epithelial cells, an EZH2 complex that included EED and SUZ12 associated with the DAB2IP promoter and increased promoter occupancy by methylated H3K27 and HDAC1 (601241). Knockdown of EZH2 reduced the association of methylated H3K27 and HDAC1 with the DAB2IP promoter. Chen et al. (2005) concluded that DAB2IP is a target for EZH2-mediated gene silencing in prostate epithelium.
Ezhkova et al. (2009) found that expression of Ezh2 in mouse epidermal progenitor cells diminished concomitant with their embryonic differentiation and postnatal decline in proliferative activity. Conditional knockout of Ezh2 in basal keratinocytes resulted in thickened stratum corneum and granular layer and precocious acquisition of epidermal barrier function in the embryo. Molecularly, these changes correlated with global reduction of H3K27 trimethylation marks and specifically with derepression of a 2-Mb epidermal differentiation complex controlled by Ink4a (CDKN2A; 600160)/Ink4b (CDKN2B; 600431). Reduced histone modification at this locus permitted recruitment of the AP1 transcription factor (see 165160) and expression of genes associated with epidermal differentiation.
Using predominantly a mouse tumor model and genetic manipulation of human prostate cancer cells, Min et al. (2010) showed that direct EZH2-mediated downregulation of DAB2IP induced an epithelial-to-mesenchymal transition (EMT) in the cancer cells and increased their metastatic potential. DAB2IP downregulation activated RAS (HRAS; 190020) and NFKB (see 164011). RAS activation drove cell growth, while NFKB activation triggered EMT and metastasis. Min et al. (2010) found an inverse relationship between EZH2 and DAB2IP expression in human prostate cancer tissues and an inverse relationship between DAB2IP expression and tumor grade. Min et al. (2010) concluded that epigenetic suppression of DAB2IP by EZH2 is a major mechanism of DAB2IP inactivation in human prostate cancer and increases metastatic potential.
Xu et al. (2011) isolated mouse embryonic endoderm cells and assessed histone modifications at regulatory elements of silent genes that are activated upon liver or pancreas fate choices, and found that the liver and pancreas elements have distinct chromatin patterns. Furthermore, the histone acetyltransferase P300 (602700), recruited via bone morphogenetic protein (BMP; see 600799) signaling, and the histone methyltransferase Ezh2 have modulatory roles in the fate choice. Xu et al. (2011) concluded that their studies revealed a functional 'prepattern' of chromatin states within multipotent progenitors and potential targets to modulate cell fate induction.
Xu et al. (2012) found that the oncogenic function of EZH2 in cells of castration-resistant prostate cancer (see 176807) is independent of its role as a transcriptional repressor. Instead, it involves the ability of EZH2 to act as a coactivator for critical transcription factors including the androgen receptor (313700). This functional switch is dependent on phosphorylation of EZH2 and requires an intact methyltransferase domain.
Di Meglio et al. (2013) investigated the role of histone methyltransferase Ezh2 in tangential migration of mouse precerebellar pontine nuclei, the main relay between neocortex and cerebellum. By counteracting the sonic hedgehog (see 600725) pathway, Ezh2 represses netrin-1 (601614) in dorsal hindbrain, which allows normal pontine neuron migration. In Ezh2 mutants, ectopic netrin-1 derepression resulted in abnormal migration and supernumerary nuclei integrating in brain circuitry. Moreover, intrinsic topographic organization of pontine nuclei according to rostrocaudal progenitor origin was maintained throughout migration and correlated with patterned cortical input. Ezh2 maintains spatially restricted Hox expression, which, in turn, regulates differential expression of the repulsive receptor Unc5b (607870) in migrating neurons; together, they generate subsets with distinct responsiveness to environmental netrin-1. Thus, Di Meglio et al. (2013) concluded that Ezh2-dependent epigenetic regulation of intrinsic and extrinsic transcriptional programs controls topographic neuronal guidance and connectivity in the cortico-ponto-cerebellar pathway.
Fillmore et al. (2015) demonstrated that EZH2 inhibition has differential effects on the TopoII inhibitor response of nonsmall-cell lung cancers in vitro and in vivo. EGFR (131550) and BRG1 (603254) mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumors respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis, and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wildtype tumors upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumors are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1.
Peng et al. (2015) used human ovarian cancers to demonstrate that EZH2-mediated histone H3 lysine-27 trimethylation (H3K27me3) and DNMT1 (126375)-mediated DNA methylation repress the tumor production of TH1-type chemokines CXCL9 (601704) and CXCL10 (147310), and subsequently determine effector T-cell trafficking to the tumor microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumor infiltration, slows down tumor progression, and improves the therapeutic efficacy of PDL1 (PDCD1LG1; 605402) checkpoint blockade and adoptive T-cell transfusion in tumor-bearing mice. Moreover, tumor EZH2 and DNMT1 are negatively associated with tumor-infiltrating CD8+ T cells and patient outcome. Thus, Peng et al. (2015) concluded that epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumors.
Using mouse embryonic stem cells (ESCs), Maier et al. (2015) confirmed interaction between 2 major repressive histone methyltransferase complexes, PRC2 and G9a (EHMT2; 604599)-Glp (EHMT1; 607001). Moreover, the complexes shared several interaction partners, including Znf518a (617733) and Znf518b (617734). In vitro, Znf518b interacted directly with G9a and with the 2 alternative PRC2 methyltransferase subunits, Ezh1 and Ezh2. Knockdown of Znf518b in mouse ESCs reduced global H3K9 dimethylation. Maier et al. (2015) concluded that ZNF518B may mediate association between PRC2 and G9A-GLP and regulate G9A-GLP activity.
Somatic Mutations
Nikoloski et al. (2010) identified heterozygous acquired (somatic) deletions at chromosome 7q36.1 encompassing the EZH2 and CUL1 (603134) genes in bone marrow cells derived from 13 of 102 individuals with myelodysplastic syndromes (252270). Two additional affected individuals had uniparental disomy (UPD) of this region. Genomic analysis of the remaining allele in 1 patient showed no aberrations in CUL1, but a truncating mutation in EZH2. Further sequencing of the EZH2 gene identified somatic mutations in 8 (26%) of 126 individuals, including the original 102 individuals. Three individuals had biallelic mutations. Collectively, 23% of affected individuals had deletions and/or point mutations in the EZH2 gene, and 40% of these individuals also had defects in the TET2 gene (612839). Individuals with defects at chromosome 7q showed significantly worse survival compared to those without these defects. The findings suggested that EZH2 may act as a tumor suppressor gene in some cases, and likely influences epigenetic modifications that may lead to cancer, since EZH2 functions as a histone methyltransferase.
Ernst et al. (2010) found that 9 of 12 individuals with myelodysplastic/myeloproliferative neoplasms and acquired UPD encompassing chromosome 7q36 also had a homozygous EZH2 mutation. Further sequencing of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 of 219, 12%) and in those with myelofibrosis (4 of 30, 13%). Several patients had refractory anemia, suggesting that somatic acquisition of these abnormalities may be an early event in the disease process. The mutations identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 can act as a tumor suppressor for myeloid malignancies.
Morin et al. (2010) identified recurrent somatic mutations affecting the tyr641 residue in exon 15 of the conserved EZH2 SET domain in cases of follicular lymphoma and diffuse large B-cell lymphoma of only the germinal-center B-cell subtype (see 605027). In vitro functional analysis showed that all 4 tyr641 mutants had an approximately 7-fold reduction in methylation ability.
Makishima et al. (2010) analyzed the EZH2 gene in 344 patients with myeloid malignancies, of whom 15 had UDP7q, 30 had del(7q), and 299 had no loss of heterozygosity of chromosome 7. They found 4 different EZH2 mutations in 3 (20%) of 15 patients with UDP7q and in 2 (7%) of 30 patients with del(7q); in 1 patient without LOH7q, a heterozygous frameshift mutation was identified. All were somatic mutations located in exon 18 or 19, coding for the SET domain of the EZH2 gene. Makishima et al. (2010) noted that alterations at tyr641, previously identified in B-cell lymphoma patients (Morin et al., 2010), were not found in any of the patients screened.
Ntziachristos et al. (2012) reported the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 (606245) genes, which encode crucial components of PRC2, in 25% of T-ALLs (613065). To further study the role of PRC2 in T-ALL, Ntziachristos et al. (2012) used NOTCH1 (190198)-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark lys27 trimethylation of histone-3 (H3K27me3) by antagonizing the activity of PRC2. Ntziachristos et al. (2012) concluded that their studies suggested a tumor suppressor role for PRC2 in human leukemia and suggested a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.
McCabe et al. (2012) found that specific, direct inhibition of EZH2 methyltransferase activity may be effective in treating EZH2 mutant lymphomas. GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecular inhibitor of EZH2 methyltransferase activity, decreased global H3K27me3 levels and reactivated silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant germinal-center B-cell subtype of diffuse large B-cell lymphoma (DLBCL) xenografts in mice.
Weaver Syndrome
Gibson et al. (2012) performed exome sequencing in 2 unrelated patients with Weaver syndrome (WVS; 277590) and their 4 unaffected parents. In both patients, heterozygous de novo mutations were identified in the EZH2 gene (Y153del, 601573.0001 and H694Y, 601573.0002, respectively); the presence of the mutations and their de novo status were confirmed by Sanger sequencing. Sequencing of EZH2 in a third patient with Weaver syndrome revealed heterozygosity for another de novo missense mutation (P132S; 601573.0003). Gibson et al. (2012) noted that a somatic mutation at his694 had previously been found in chronic myelomonocytic leukemia, as well as mutations in nearby residues at positions 690 and 693 in other hematologic malignancies (Makishima et al., 2010). Given that patients with Weaver syndrome had been reported to develop tumors or malignancies, including acute lymphoblastic leukemia, Gibson et al. (2012) suggested that constitutive EZH2 mutations might confer a mild predisposition to malignancy.
Tatton-Brown and Rahman (2013) reviewed the similarities and differences between the NSD1 (606681) and EZH2 genes, which cause the overgrowth Sotos and Weaver syndromes, respectively. The authors stated that 3 mutations that had been identified somatically in myeloid malignancies had been shown to cause Weaver syndrome when present constitutionally, but that none of the Weaver syndrome patients had as yet developed malignancies. The reason for the divergent phenotypes was unclear.
In 4 patients with classic features of Weaver syndrome, Tatton-Brown et al. (2011) identified heterozygous mutations in the EZH2 gene (see, e.g., 601573.0004-601573.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in 7 parental samples available for study, establishing that the mutations were de novo in at least 3 of the patients. Tatton-Brown et al. (2011) noted that the mutations in 2 of these patients (R684C, 601573.0004 and Y733X, 601573.0005) had also been detected as somatic mutations in CMML and myelofibrosis by Ernst et al. (2010). Tatton-Brown et al. (2011) performed Sanger sequencing of the coding sequence and intron-exon boundaries of the EZH2 gene in an additional 300 patients with a clinical diagnosis of Weaver syndrome or with a nonspecific overgrowth syndrome defined as having height or head circumference at least 2 standard deviations above the mean, together with variable additional phenotypic features. Variants considered to be pathogenic were seen in 15 of the 300 patients, but the phenotype in most of the 15 patients was not stated; 9 of the mutations were de novo, 1 (K156E) was inherited in a family (case 2) with nonspecific overgrowth with full segregation with the phenotype, and 5 had unknown inheritance. Among the 19 patients identified with EZH2 mutations, the most prominent finding was increased height with all being at least 2 SD above the mean and 9 patients being over 4 SD above the mean. The increase in head circumference was less dramatic. Learning disability was frequent, with most in the mild to moderate range and some with no reported learning difficulties.
In mice, the Ezh2 polycomb group protein is most abundant at sites of embryonic lymphopoiesis. In humans, EZH2 is upregulated in proliferating germinal center B cells. Ezh2-deficient mice suffer early embryonic death (O'Carroll et al., 2001). Using Cre-loxP conditional mutagenesis, Su et al. (2003) demonstrated that Ezh2 controls B-cell development through the regulation of histone H3 (see 601128) methylation and immunoglobulin heavy chain (IGH; see 147100) rearrangement. They proposed that EZH2-dependent histone H3 methylation leads to chromatin modification required for normal IGH rearrangement, which is critical for early B-cell development.
Increased expression of Cdkn2a (600160), which encodes p16(Ink4a) and p19(Arf) isoforms, limits regeneration of pancreatic beta cells in aging mice. Chen et al. (2009) showed that Ezh2 repressed Cdkn2a in islet beta cells. Ezh2 levels declined in aging islet beta cells, and this attrition coincided with reduced histone H3 trimethylation at Cdkn2a and increased levels of p16(Ink4a) and p19(Arf). Conditional deletion of beta-cell Ezh2 in juvenile mice also reduced H3 trimethylation at the Cdkn2a locus, leading to precocious increased p16(Ink4a) and p19(Arf) levels. These mutant mice had reduced beta-cell proliferation and mass, hypoinsulinemia, and mild diabetes, phenotypes that could be rescued by germline deletion of Cdkn2a. Destruction of beta cells with streptozotocin in wildtype mice increased Ezh2 expression, accompanied by adaptive beta-cell proliferation and reestablishment of beta-cell mass. In contrast, mutant mice treated similarly failed to regenerate beta cells, resulting in lethal diabetes. Chen et al. (2009) concluded that EZH2 is required for epigenetic repression of CDKN2A and normal beta-cell expansion, and that failure of beta-cell regeneration leads to diabetes.
Delgado-Olguin et al. (2012) found that conditional deletion of Ezh2 in mouse anterior heart field resulted in right cardiac hypertrophy and fibrosis after birth. Gene expression profiling of Ezh2-knockout hearts revealed derepression of Six1 (601205), with concomitant activation of Six1-dependent skeletal muscle-specific genes. Overexpression of Six1 in cultured neonatal mouse cardiomyocytes resulted in hypertrophy comparable to that induced by the hypertrophic agonist endothelin-1 (EDN1; 131240). Knockdown of Six1 in Ezh2-knockout hearts completely rescued the cardiac phenotype.
In a 30-year-old man (patient 1) with Weaver syndrome (WVS; 277590), originally reported by Weaver et al. (1974), Gibson et al. (2012) identified heterozygosity for a de novo 3-bp deletion at nucleotide 457 (457_459del) in exon 5 of the EZH2 gene, resulting in deletion of a tyrosine residue at codon 153 (tyr153del).
In an 11-year-old girl with Weaver syndrome (WVS; 277590), Gibson et al. (2012) identified heterozygosity for a de novo 2080C-T transition in exon 18 of the EZH2 gene, resulting in a his694-to-tyr (H694Y) substitution within the knot substructure of the active site of the SET domain, predicted to disrupt binding of the enzymatic cofactor S-adenosyl-L-methionine.
In a 19-year-old woman with Weaver syndrome (WVS; 277590), Gibson et al. (2012) identified heterozygosity for a de novo 394C-T transition in exon 5 of the EZH2 gene, resulting in a pro132-to-ser (P132S) substitution.
In a patient (case 10) with classic features of Weaver syndrome (WVS; 277590), Tatton-Brown et al. (2011) identified a heterozygous c.2050C-T transition in the EZH2 gene, resulting in an arg684-to-cys (R684C) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The one parent who was available for testing did not have the mutation.
In a patient (case 14) with classic features of Weaver syndrome (WVS; 277590), Tatton-Brown et al. (2011) identified a de novo heterozygous c.2199C-G transversion in the EZH2 gene, resulting in a tyr733-to-ter (Y733X) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
In a patient (case 16) with classic features of Weaver syndrome (WVS; 277590), Tatton-Brown et al. (2011) identified a de novo heterozygous 8-bp duplication (c.2204_2211dupAGGCTGAT) in the EZH2 gene, predicted to result in a frameshift and a premature stop codon. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
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