Imagawa–Matsumoto syndrome: SUZ12‐related overgrowth disorder

Abstract

The SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively. Clinical manifestations of these syndromes significantly overlap, although their different prevalence rates have recently been noted: generalized overgrowth, intellectual disability, scoliosis, and excessive loose skin appear to be less prevalent in IMMAS than in the other two syndromes. We could not determine any apparent genotypephenotype correlation in IMMAS. The phenotype of neurofibromatosis type 1 arising from NF1 deletion was also shown to be modified by the deletion of SUZ12, 560 kb away. This review deepens our understanding of the clinical and genetic characteristics of IMMAS together with other overgrowth syndromes related to PRC2. We also report on a novel IMMAS patient carrying a splicing variant (c.1023+1G>C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.

BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system

“…Our ENS observations may be relevant to a broad range of human neurodevelopmental and neurodegenerative diseases because BAP1 impacts PRC activity ( 17 , 18 ). EZH2 , EED2 , and SUZ12 mutations cause the neurodevelopmental disorders Weaver syndrome (OMIM #277590) ( 28 ), Cohen-Gibson syndrome (OMIM #617561) ( 30 ), and Imagawa-Matsumoto syndrome (OMIM #618786) ( 29 ). Mutations in EZH1 ( 27 ) and in KDM6B (OMIM #611577) ( 32 ) and KDM6A ( 31 ) (H3K27 demethylases) cause syndromic neurodevelopmental disorders and Kabuki syndrome (OMIM #147920 and #300867).…”

May the force be with you: Nuclear condensates function beyond transcription control

“…Weaver syndrome (WS) EZH2 EZH2 Components of the PRC2 Overgrowth and macrocephaly [48] Cohen-Gibson syndrome (COGIS) EED EED [49] Imagawa-Matsumoto syndrome (IMMAS) SUZ12 SUZ12 [50] Pathogenic variants in NIPBL were identified as the most frequent (70%) cause of CdLS. Further studies led to the detection of variants in six additional genes causal of CdLS: SMC1A (5%), SMC3 (1%), RAD21 (1%), BRD4 (<1%), HDAC8 (<1%), and ANKRD11 (<1%).…”

“…During the last 10 years, EZH2, EED, and SUZ12 genes were found to be responsible for the WS, COGIS, and IMMAS syndromes, respectively. [48][49][50] (Table 1). The three genes encode for core components of the PRC2, and pathogenic mutations result in the loss-of-function of the gene.…”

Overgrowth syndromes, diagnosis and management

“…Imagawa–Matsumoto syndrome involves SUZ12 , a component of the PRC2 complex, which facilitates the addition of methyl groups to histone proteins. SUZ12 collaborates with core PRC2 components EZH2, EED, and RBAP48 to catalyze methylation at lysine 27 on histone H3 (H3K27), resulting in H3K27 methylation modification [26]. Notably, Beckwith-Wiedemann syndrome sheds light on the connection between epigenetic dysregulation and growth disorders.…”