Rare SUZ12 variants commonly cause an overgrowth phenotype

Area of Science:

• Genetics
• Epigenetics
• Developmental Biology

Background:

• Polycomb repressive complex 2 (PRC2) is crucial for gene silencing.
• Pathogenic variants in PRC2 components cause Weaver and Cohen-Gibson overgrowth syndromes.
• SUZ12 is a key component of the PRC2 complex.

Purpose of the Study:

• To investigate the role of rare heterozygous SUZ12 variants in causing overgrowth syndromes.
• To characterize the phenotype associated with SUZ12 variants.

Main Methods:

• Clinical evaluation of 10 patients from nine families with rare heterozygous SUZ12 variants.
• Genomic analysis to identify and classify SUZ12 variants (frameshift, missense, nonsense, splice site).

Main Results:

• All 10 patients presented with a Weaver-like phenotype.
• Observed features included variable overgrowth, dysmorphic features, musculoskeletal abnormalities, and developmental delay/intellectual disability.
• Genitourinary, brain, and respiratory abnormalities were also noted in some patients.

Conclusions:

• Rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and neurodevelopmental issues in heterozygotes.
• SUZ12 variants can be de novo or inherited, sometimes from mildly affected parents.
• Further research with larger cohorts is needed to define distinct SUZ12-related syndromes.