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

backgroundImagawa-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.

methodsTrio-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.

resultsThe 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.

conclusionsWe 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.