Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome.

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Weaver syndrome (WS) is a rare congenital overgrowth disorder.
• Mutations in EZH2 or EED, core components of the polycomb repressive complex 2 (PRC2), are known causes of WS.
• PRC2 catalyzes histone H3 lysine 27 trimethylation, crucial for gene regulation.

Purpose of the Study:

• To investigate the genetic basis of Weaver syndrome in suspected cases.
• To identify novel mutations in genes associated with PRC2 function.
• To understand the functional consequences of identified mutations on PRC2 activity.

Main Methods:

• Whole-exome sequencing was performed on eight probands with clinically suspected WS.
• Identified mutations were analyzed for their impact on PRC2 components (EZH2, EED, SUZ12).
• In vitro functional assays were used to assess the effect of mutations on histone methyltransferase activity.

Main Results:

• Three novel mutations were identified: a deletion in EZH2/CUL1, a missense mutation in EED, and a missense mutation in SUZ12.
• The SUZ12 mutation was found to be mosaic in one individual's father.
• Both EED and SUZ12 missense mutations resulted in decreased histone H3 lysine 27 trimethylation.
• Germline SUZ12 mutations were reported for the first time in humans.

Conclusions:

• Loss-of-function mutations in PRC2 components are a significant cause of Weaver syndrome.
• The study expands the spectrum of genetic causes for WS, including mutations in SUZ12.
• Functional analyses confirm the pathogenic mechanism involving impaired histone methylation.