SUZ12 – Imagawa-Matsumoto Syndrome

Imagawa-Matsumoto syndrome (IMMAS) is an autosomal dominant overgrowth disorder characterized by macrocephaly, round face, broad forehead, hypertelorism, musculoskeletal anomalies, agenesis of the corpus callosum, polymicrogyria, and developmental delay. Heterozygous loss-of-function of SUZ12, a core component of the Polycomb Repressive Complex 2 (PRC2), has been identified as the genetic basis of IMMAS through both microdeletion and splice-site variants. Clinical manifestations overlap with other PRC2-related syndromes such as Weaver and Cohen-Gibson syndromes, yet IMMAS shows lower prevalence of generalized overgrowth and intellectual disability compared to its allelic disorders (PMID:36645289).

Genetic evidence for SUZ12 in IMMAS includes a de novo 1.5-Mb deletion at chromosome 17q11.2 encompassing SUZ12 in a Turkish patient (PMID:39258127) and a heterozygous de novo splice-site variant c.1023+>C) identified in an unrelated proband (PMID:36645289). To date, 14 unrelated probands have been reported with distinct SUZ12 variants, all confirmed de novo, establishing a recurrent genetic cause without familial segregation beyond the index cases (PMID:36645289; PMID:39258127).

The pathogenic mechanism is consistent with haploinsufficiency: SUZ12 is essential for PRC2-mediated trimethylation of histone H3 lysine 27 (H3K27me3), a key epigenetic mark for gene repression. Suz12 knockout mice exhibit early embryonic lethality and loss of di- and trimethylated H3K27, mirroring disrupted PRC2 activity in human IMMAS (PMID:15385962). In vitro knockdown of SUZ12 also reduces H3K27me3 and impairs PRC2 function at target loci, demonstrating concordant molecular deficits (PMID:15225548).

No studies to date have reported conflicting evidence undermining the SUZ12–IMMAS association. The consistent overlap of clinical features with other PRC2-related syndromes and the recurrence of de novo SUZ12 variants support a direct causal relationship.

Integration of genetic and functional data confirms that SUZ12 haploinsufficiency disrupts PRC2 function, leading to dysregulated developmental gene silencing and the characteristic overgrowth and neurodevelopmental phenotypes of IMMAS. Additional deep-phenotyping and functional assays will further refine genotype–phenotype correlations and guide targeted therapeutic strategies.

Key Take-Home: Heterozygous de novo SUZ12 loss-of-function variants cause Imagawa-Matsumoto syndrome via PRC2 haploinsufficiency, providing a clear diagnostic target and underpinning future genotype-driven management.

References

• Clinical genetics • 2023 • Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder. PMID:36645289
• Noro psikiyatri arsivi • 2024 • Imagawa-Matsumoto Syndrome: The First Case From Turkey. PMID:39258127
• The EMBO journal • 2004 • Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. PMID:15385962
• Molecular cell • 2004 • SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. PMID:15225548

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