Weaver syndrome: genes and variants

Genes linked to Weaver syndrome

• EZH2: Histone-lysine N-methyltransferase EZH2

  It deposits repressive H3K27 trimethylation through Polycomb repressive complex 2 and thereby maintains cell-identity and developmental gene silencing. Activating variants drive some germinal-center lymphomas, while germline gain- or loss-of-function variants can cause overgrowth or developmental syndromes.

  12 disease-causing and 64 uncertain variants in EZH2 are linked to Weaver syndrome.

• EZH1: Histone-lysine N-methyltransferase EZH1

  It provides H3K27 methyltransferase activity in Polycomb repressive complex 2 and helps maintain transcriptional repression, particularly in differentiated and quiescent cells. Dysregulation can influence stem-cell function and cancer biology, but strong monogenic human disease associations remain limited.

  0 disease-causing and 0 uncertain variants in EZH1 are linked to Weaver syndrome.

• NSD1: Histone-lysine N-methyltransferase, H3 lysine-36 specific

  It regulates developmental transcription through chromatin modification, including H3K36 methylation. Haploinsufficiency causes Sotos syndrome with childhood overgrowth, characteristic facial features, and developmental delay, while somatic rearrangements occur in some leukemias.

  0 disease-causing and 0 uncertain variants in NSD1 are linked to Weaver syndrome.

Weakly linked (only a few uncertain records): SUZ12.

Where Weaver syndrome variants cluster

• EZH2 SET (positions 612–727): 8 of 12 disease-causing changes, 4.3× more than its size predicts.

Known disease-causing variants in Weaver syndrome

Which prediction tools work for Weaver syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MutPred2: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• MetaLR: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Weaver syndrome

• Sotos syndrome, also linked to NSD1
• Acute myeloid leukemia, also linked to NSD1
• Beckwith-Wiedemann syndrome, also linked to NSD1
• Marfanoid habitus and intellectual disability, also linked to NSD1
• Holoprosencephaly, also linked to NSD1

Frequently asked questions

Which genes are linked to Weaver syndrome?

In CATVariant, Weaver syndrome is linked to 3 analyzed proteins: EZH2 (Histone-lysine N-methyltransferase EZH2), EZH1 (Histone-lysine N-methyltransferase EZH1) and NSD1 (Histone-lysine N-methyltransferase, H3 lysine-36 specific).

How many genetic variants are linked to Weaver syndrome?

94 variants: 12 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 65 are of uncertain significance or have conflicting reports.

Which uncertain variants in Weaver syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Weaver syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.86, based on 11 disease-causing and 255 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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