DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Area of Science:

• Genetics
• Epigenetics
• Molecular Biology

Background:

• Weaver syndrome (WS) is an overgrowth/intellectual disability syndrome (OGID).
• Pathogenic variants in EZH2, a core component of Polycomb repressive complex-2 (PRC2), cause WS.
• EZH2 encodes a histone methyltransferase crucial for gene regulation.

Purpose of the Study:

• To identify a DNA methylation (DNAm) signature for Weaver syndrome.
• To assess the signature's utility in classifying EZH2 variants and diagnosing OGID.
• To explore the signature's potential for classifying variants in other PRC2 components (EED, SUZ12).

Main Methods:

• Genome-wide DNA methylation analysis was performed on 187 individuals with OGID and 969 controls.
• Statistical analysis was used to identify a specific DNAm signature associated with WS.
• The signature's ability to distinguish variant types and predict pathogenic variants was evaluated.

Main Results:

• A highly specific and sensitive DNAm signature for WS was identified, linked to pathogenic EZH2 variants.
• The signature accurately distinguished loss-of-function from gain-of-function EZH2 variants.
• The DNAm signature successfully predicted pathogenic variants in EED and SUZ12 and identified undiagnosed OGID cases.

Conclusions:

• A functionally relevant DNAm signature for WS and related PRC2 gene variants has been discovered.
• This signature demonstrates significant potential for diagnostic classification in OGID.
• The findings support the integration of DNAm signatures into diagnostic and translational research for genetic disorders.