EZH2 – Weaver Syndrome

Weaver syndrome is a rare autosomal dominant overgrowth/intellectual disability syndrome characterized by pre- and postnatal tall stature, advanced bone age, macrocephaly and variable developmental delay. Heterozygous germline mutations in the enhancer of zeste homolog 2 (EZH2) gene underlie the disorder through epigenetic dysregulation of H3K27 trimethylation (HGNC:3527; MONDO:0010193).

Clinical Validity

Trio-based whole-exome sequencing identified three de novo EZH2 missense or small indel variants in unrelated Weaver syndrome probands (e.g., c.394C>T (p.Pro132Ser)) (PMID:22177091) and Sanger sequencing of larger cohorts confirmed EZH2 mutations in over 48 individuals (PMID:24214728). Multiple families show de novo occurrence without parental transmission, consistent with autosomal dominant inheritance.

Genetic Evidence

Inheritance is autosomal dominant. Over 50 unrelated probands harbor heterozygous EZH2 variants, including missense, small in-frame deletions, and rare truncating alleles clustered in the SET domain and catalytic region. Recurrent hotspots include codons 684–695 and codon 626. No evidence for founder effects; all variants appear de novo or arise independently in affected individuals.

Functional / Experimental Evidence

In vitro reconstitution of PRC2 complexes carrying Weaver syndrome-associated variants (e.g., c.553G>C (p.Asp185His), c.2050C>T (p.Arg684Cys)) demonstrates significantly reduced H3K27 methyltransferase activity compared to wild type (PMID:26694085). Structural studies of the EZH2 SET domain reveal autoinhibitory conformations that are relieved upon complex formation, explaining loss of function in mutant proteins (PMID:24367637).

Model Organism and Rescue

A CRISPR/Cas9 mouse model carrying the recurrent c.1876G>A (p.Val626Met) variant recapitulates Weaver syndrome features: heterozygotes show mild overgrowth and advanced bone parameters, while homozygotes are perinatally lethal. Both heterozygous and homozygous embryos exhibit decreased H3K27me3, and pharmacologic inhibition of KDM6A/6B reverses excessive osteogenesis in mutant cells (PMID:29244146; PMID:37425751).

Mechanism and Clinical Utility

Collectively, genetic and experimental data support haploinsufficiency/partial loss-of-function of EZH2 as the mechanism driving Weaver syndrome. EZH2 sequencing should be performed in patients with tall stature, accelerated skeletal maturation, macrocephaly and developmental delay to confirm diagnosis, inform prognosis and guide surveillance for associated malignancies.

Key Take-home: Pathogenic heterozygous EZH2 variants cause Weaver syndrome via impaired H3K27 trimethylation; genetic testing provides definitive diagnosis and enables tailored management.

References

• American Journal of Human Genetics | 2012 | Mutations in EZH2 cause Weaver syndrome PMID:22177091
• American Journal of Medical Genetics Part A | 2013 | Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype PMID:24214728
• Human Mutation | 2016 | Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro PMID:26694085
• The Journal of Clinical Endocrinology & Metabolism | 2018 | Ezh2 Mutations Found in the Weaver Overgrowth Syndrome Cause a Partial Loss of H3K27 Histone Methyltransferase Activity PMID:29244146
• bioRxiv (preprint) | 2023 | Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition PMID:37425751

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