EZH2 was first reported in relation to autosomal dominant Weaver syndrome in 2011 (PMID: 22190405). Weaver syndrome (WS) is a rare multisystem disorder characterized by tall stature, a typical facial appearance, and variable intellectual disability. Additional features may include camptodactyly, advanced bone age, soft doughy skin, umbilical hernia, and a low hoarse cry (PMIDs: 22190405, 23865096, 24214728). EZH2 variants have also been observed in individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome (PMIDs: 22190405, 24214728). EZH2 variants, primarily missense, as well as a small number of nonsense, frameshift, and in-frame insertion or deletion variants, have been identified in over 50 individuals with Weaver syndrome or overgrowth (PMIDs: 22177091, 22190405, 24214728, 32243864). Truncating variants are uncommon and to date have only been identified in the last or penultimate exon (PMID: 24214728, ClinVar variation ID: 207471). Only 11 probands are included in this curation because the maximum score for genetic evidence has been reached.
EZH2 encodes a histone methyltransferase. Pathogenic variants in EZH2 generate a highly specific DNA methylation signature (PMID: 32243864). The disease mechanism is loss of function (PMIDs: 26694085, 29244146, 32243864). However, the fact that truncating variants have only been reported in the last or penultimate exon and may therefore escape nonsense-mediated decay suggests that they may not act through haploinsufficiency (PMID: 22190405, 24214728). This gene-disease relationship is also supported by experimental evidence, including protein interaction, functional alterations, and mouse model studies (PMIDs: 15225548, 26694085, 29244146, 32243864).
In summary, there is definitive evidence supporting the relationship between EZH2 and Weaver syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 3, 2022 (SOP Version 9).
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