Submission Details

EED was first reported in relation to autosomal dominant Cohen-Gibson syndrome in 2015 (Cohen et al., PMID: 25787343). Cohen-Gibson syndrome is an overgrowth disorder characterized by increased somatic growth parameters with neonatal onset and variable intellectual disability. Affected individuals have dysmorphic facial features, advanced bone age, and skeletal abnormalities, including flaring of the metaphyses of the long bones, large hands with long fingers and camptodactyly, and often scoliosis or cervical spine anomalies. Other features may include hypotonia, difficulty walking due to skeletal anomalies, and umbilical hernia (PMID: 27868325).

Nine variants (8 missense and one insertion-deletion) that primarily arise de novo or are assumed de novo have been reported in 11 probands in 8 publications (PMIDs: 25787343, 27193220, 27868325, 28229514, 28475857, 29410511, 30793471, 30858506) and are included in this curation. Though all variants reported to date have been missense, loss of function has been postulated as the mechanism of disease as a functional copy of EED is essential for proper EZH2-mediated methyltransferase activity at H3K27 via the polycomb repressive complex 2 (PRC2). This was supported by western blotting of H3K27me3 as a marker of PRC2 methyltransferase activity; wild-type EED rescued normal levels of H3K27me3 whereas at least two reported missense variants failed to do so (PMID: 28229514). This gene-disease relationship is also supported by biochemical function in the PRC2 which maintains gene silencing to play a role in neurogenesis and embryogenesis, and protein interaction with EZH2 to support methyltransferase activity (PMIDs: 9584199, 15225548, 27578866).

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2022 (SOP Version 9).

EED was first reported in relation to autosomal dominant Cohen-Gibson syndrome in 2015 (Cohen et al., PMID: 25787343). Cohen-Gibson syndrome (COGIS) is an overgrowth disorder characterized by increased somatic growth parameters with neonatal onset and variable intellectual disability. Affected individuals have dysmorphic facial features, advanced bone age, and skeletal abnormalities, including flaring of the metaphyses of the long bones, large hands with long fingers and camptodactyly, and often scoliosis or cervical spine anomalies. Other features may include hypotonia, difficulty walking due to skeletal anomalies, and umbilical hernia (Cooney et al., 2017). Nine variants (missense and one insertion-deletion) that primarily arise de novo or assumed de novo have been reported in 11 probands in 8 publications (PMIDs: 25787343, 27193220, 27868325, 28229514, 30793471, 29410511, 30793471, 30858506) and are included in this curation. Though all variants reported to date have been missense, loss of function has been postulated as the mechanism of disease as a functional copy of EED is essential for proper EZH2-mediated methyltransferase activity at H3K27 via the polycomb repressive complex 2 (PRC2). This was supported by western blotting of H3K27me3 as a marker of PRC2 methyltransferase activity, through which wild-type EED rescued normal levels of H3K27me3 whereas at least two reported missense variants failed to do so (PMID: 28229514). This gene-disease relationship is also supported by expression throughout the brain, biochemical function in the PRC2 which maintains gene silencing to play a role in neurogenesis and embryogenesis, and protein interaction with EZH2 to support methyltransferase activity (PMIDs: 9584199, 15225548, 27578866, 29415247). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen ID/Autism Gene Curation Expert Panel on December 6, 2022 (SOP Version 9).