Identification and functional characterization of a SUZ12 frameshift variant in a Chinese family with Imagawa-Matsumoto syndrome.

BACKGROUND: Imagawa-Matsumoto syndrome (IMMAS) is a rare overgrowth disorder caused by heterozygous loss-of-function variants in SUZ12, which encodes a core subunit of the Polycomb Repressive Complex 2 (PRC2). To date, fewer than 20 cases have been reported, and the molecular mechanisms underlying PRC2 dysfunction in IMMAS remain incompletely understood. METHODS: Trio-based whole-exome sequencing (Trio-WES) was performed in a Chinese family presenting with overgrowth and dysmorphic features. The candidate variant was validated by Sanger sequencing and segregation analysis. AlphaFold 3 was used to predict the structural consequences of the variant. In vitro overexpression and protein assays were conducted to evaluate SUZ12 protein expression and subcellular localization. RESULTS: The proband exhibited global developmental delay, macrocephaly, hypertrichosis, and distinctive craniofacial dysmorphism. Trio-WES identified a heterozygous frameshift variant in SUZ12 (c.1244_1248del; p.Glu415GlyfsTer5). Computational modeling predicted that the truncating variant removes the ZnF and VEFS domains and may affect the predicted SUZ12-EZH2 interface. In vitro expression of the mutant construct confirmed the production of a truncated SUZ12 protein. Furthermore, peripheral blood mononuclear cells (PBMCs) from both the proband and her mother showed a substantial global reduction in H3K27me3 levels, consistent with impaired PRC2-mediated histone methylation in vivo. CONCLUSIONS: We report a Chinese family with Imagawa-Matsumoto syndrome harboring a SUZ12 frameshift variant (c.1244_1248del; p.Glu415GlyfsTer5). Our study expands the phenotypic spectrum associated with this variant and provides evidence consistent with impaired PRC2-mediated histone methylation.