EED – Weaver syndrome

Weaver syndrome is a rare congenital overgrowth disorder characterized by pre- and postnatal overgrowth, macrocephaly, accelerated bone age, variable intellectual disability, and distinctive facial features. Although pathogenic variants in EZH2 were first linked to Weaver syndrome, emerging data implicate locus heterogeneity within PRC2, including heterozygous missense variants in EED, a core WD40 subunit of the complex.

Six unrelated individuals with clinical diagnoses of Weaver syndrome have been reported to carry heterozygous EED missense mutations clustered in WD40 repeats, consistent with de novo occurrence in all cases ([PMID:27868325]; [PMID:28229514]; [PMID:29410511]; [PMID:30858506]). No additional affected relatives have been described, indicating de novo inheritance rather than familial segregation.

The variant spectrum includes c.707G>C (p.Arg236Thr), c.904A>G (p.Arg302Gly), c.917_919delinsCGG (p.Arg306_Asn307delinsThrAsp), and c.581A>G (p.Asn194Ser), all mapping to key EED WD40 motifs critical for PRC2 assembly and function.

Functional assays demonstrate that EED WD40 mutations disrupt interaction with EZH2, impair trimethylation of histone H3 lysine 27 (H3K27me3) and reduce PRC2 histone methyltransferase activity, supporting a loss-of-function mechanism ([PMID:28229514]; [PMID:9742080]).

Collectively, six de novo probands with concordant functional data meet ClinGen Strong criteria for a definitive EED–Weaver syndrome association. EED testing should be included in diagnostic gene panels for overgrowth syndromes. Key Take-home: Heterozygous WD40 domain variants in EED cause Weaver syndrome via PRC2 loss-of-function, informing molecular diagnosis and potential therapeutic targeting.

References

• American journal of medical genetics. Part A | 2017 | Novel EED mutation in patient with Weaver syndrome. PMID:27868325
• Human mutation | 2017 | Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. PMID:28229514
• Journal of human genetics | 2018 | Novel de novo mutation affecting two adjacent aminoacids in the EED gene in a patient with Weaver syndrome. PMID:29410511
• Journal of human genetics | 2019 | Three additional patients with EED-associated overgrowth: potential mutation hotspots identified? PMID:30858506
• Molecular and cellular biology | 1998 | Point mutations in the WD40 domain of Eed block its interaction with Ezh2. PMID:9742080

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