EED – Cohen-Gibson syndrome

EED encodes a core component of the polycomb repressive complex 2 (PRC2), which mediates histone H3K27 methylation and transcriptional repression. Heterozygous missense variants in EED have been causally linked to Cohen-Gibson syndrome, a rare overgrowth disorder with intellectual disability.

Genetic evidence comprises at least 12 unrelated probands with heterozygous EED missense variants affecting the WD40 repeat domain (PMID:34533271) and three additional affected relatives segregating the recurrent c.581A>G (p.Asn194Ser) variant in a single pedigree (PMID:37840385). These variants arose de novo in most cases, consistent with an autosomal dominant inheritance mode. The c.581A>G (p.Asn194Ser) alteration has been observed in three independent unrelated individuals and in all three affected members of one family, highlighting a mutational hotspot in the WD40 domain.

Clinically, affected individuals present with fetal or early childhood overgrowth (HP:0001548), moderate intellectual disability (HP:0002342), seizures (HP:0001250), scoliosis, and variable dysmorphic features. Phenotypic expressivity ranges from mild to severe, even among carriers of identical variants, underscoring clinical heterogeneity in Cohen-Gibson syndrome.

Functional assays demonstrate that WD40 domain missense mutants of EED abrogate its binding to EZH2 and disrupt PRC2 complex formation, leading to global reduction of H3K27 methylation (PMID:9742080, PMID:17997413). These mechanistic studies support a dominant-negative or haploinsufficiency mechanism underlying disease pathogenesis.

In summary, robust genetic and experimental concordance classify the EED–Cohen-Gibson syndrome association as Strong according to ClinGen criteria. Genetic testing for EED variants is recommended in patients with syndromic overgrowth and neurodevelopmental anomalies.

References

• American journal of medical genetics. Part A • 2022 • Manifestation of epilepsy in a patient with EED-related overgrowth (Cohen-Gibson syndrome). PMID:34533271
• American journal of medical genetics. Part A • 2024 • EED related overgrowth: First report of multiple members in a single family. PMID:37840385
• Molecular and cellular biology • 1998 • Point mutations in the WD40 domain of Eed block its interaction with Ezh2. PMID:9742080
• Journal of molecular biology • 2007 • Molecular and functional mapping of EED motifs required for PRC2-dependent histone methylation. PMID:17997413

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