• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit




Associated disorders

The EZH2 gene is associated with autosomal dominant Weaver syndrome (MedGen UID: 120511).

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EZH2: Sequencing analysis for exons 20 includes only cds +/- 10 bp.

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Invitae tests that include this gene:

EZH2 encodes a histone methyl transferase that a component of the polycomb group proteins that work as transcriptional repressors and play a critical role during growth and development.

EZH2-related Weaver Syndrome
MedGen UID: 120511

Clinical condition
The EZH2 gene is associated with autosomal dominant Weaver syndrome (MedGen UID: 120511). Weaver syndrome is an overgrowth disorder characterized by tall stature, advanced bone age, and macrocephaly (PMID: 23865096, 22177091, 24214728, Genetics Home Reference. Weaver syndrome. Accessed October 2016). Additional clinical features include poor coordination, soft doughy skin, ligamentous laxity, umbilical hernia, camptodactyly of the fingers or toes, scoliosis, pectus, clubbed foot, abnormal tone, and hoarse, low cry in infancy (PMID: 24214728). An increased incidence of malignancy has also been suggested but the overall risk is not well defined (PMID: 20101679, 24214728).

Weaver syndrome is associated with variable intellectual disability, ranging from mild to severe, although most cases fall in the mild range (PMID: 24214728). Neuronal migration disorders have also been detected on neuroimaging (PMID: 24214728), however, it is unclear if there is a direct correlation between the severity of brain abnormalities in this condition and the degree intellectual disability (PMID: 23865096).

Affected individuals typically have characteristic facial features including retrognathia, broad forehead, hypertelorism, large, low-set ears, and a dimpled chin (PMID: 23865096, Genetics Home Reference. Weaver syndrome. Accessed October 2016.). These features often evolve over time and are more easily identifiable in infancy and early childhood (PMID: 24214728). A wide range of clinical variability has been reported; however, tall stature is the most consistent feature (PMID: 22190405, 24214728). Weaver syndrome also has many overlapping features with Sotos syndrome, another type of overgrowth disorder (PMID: 24214728).

There is emerging evidence suggesting an association with EZH2 and neuroblastoma and therefore this gene is available as a “preliminary-evidence” gene on Invitae’s Nervous System/Brain Cancer Panel (PMID: 19011474, 20101679). Preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these limited evidence genes.

Gene information
The EZH2 gene encodes a histone methyltransferase. Histone methyltransferase methylates histones, resulting in the suppressed activity of certain genes. The EZH2 enzyme specifically forms the polycomb repressive complex-2. By selectively turning off certain genes, this complex is involved in cell fate determination (Genetics Home Reference. EZH2 gene. Accessed October 2016.).

Variants in EZH2 have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it); however, some cases are inherited from an affected parent (PMID: 22177091, 22190405).

While there are no established medical management and surveillance guidelines for Weaver syndrome, the following recommendations have been suggested (PMID: 23865096):

  • developmental assessment
  • thorough history and physical exam to identify clinical features associated with Weaver syndrome
    • particular attention should be paid to growth measurements and skeletal findings: camptodactyly (in the newborn period), scoliosis, and pectus deformities. The presence of an abdominal mass warrants immediate investigation (due to potential risk of neuroblastoma)
  • regular follow-up with a pediatrician for affected children to monitor developmental progress and assess for scoliosis, camptodactyly, and/or hypotonia
    • consideration of less frequent follow-up for older children/teenagers who do not have medical complications
  • consultation with a medical geneticist and/or genetic counselor to identify other family members who could be affected; where possible, measurement of parental heights

For individuals with developmental delay and/or learning disability, a referral for learning/behavior/speech assessment and support may be indicated. Occasionally, toe camptodactyly may require surgical intervention. Physiotherapy may also be beneficial for both camptodactyly and those with joint pain secondary to ligamentous laxity. If scoliosis is present, a referral to orthopedics for further evaluation and monitoring is appropriate. If additional clinical issues are detected through the history and/or examination, the appropriate specialist referrals should be made.

Knowing if a pathogenic EZH2 variant is present is advantageous. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and clinically relevant EZH2 data is likely to become available in the near future. Awareness of this variant encourages patients and their providers to inform at-risk family members, to consider implementing condition-specific management protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: November 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
EZH2* NM_004456.4

*EZH2: Sequencing analysis for exons 20 includes only cds +/- 10 bp.