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Intellectual disability

Gene: SUZ12

Amber List (moderate evidence)

SUZ12 (SUZ12 polycomb repressive complex 2 subunit)
EnsemblGeneIds (GRCh38): ENSG00000178691
EnsemblGeneIds (GRCh37): ENSG00000178691
OMIM: 606245, Gene2Phenotype
SUZ12 is in 6 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families, of whome 7 had mostly mild intellectual disability.
Created: 6 Aug 2020, 12:55 p.m. | Last Modified: 6 Aug 2020, 12:55 p.m.
Panel Version: 3.235

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Thirteen affected individuals from 12 families.
Created: 29 Feb 2020, 6:19 a.m. | Last Modified: 29 Feb 2020, 6:19 a.m.
Panel Version: 3.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Imagawa-Matsumoto syndrome, MIM# 618786; Intellectual disability; Overgrowth

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 may also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature
Created: 10 Dec 2019, 9:56 p.m. | Last Modified: 10 Dec 2019, 10:25 p.m.
Panel Version: 3.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Imagawa-Matsumoto syndrome 618786
Tags
for-review
OMIM
606245
Clinvar variants
Variants in SUZ12
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

6 Aug 2020, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: SUZ12 were changed from Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall to Imagawa-Matsumoto syndrome 618786

6 Aug 2020, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: suz12 has been classified as Amber List (Moderate Evidence).

6 Aug 2020, Gel status: 0

Added Tag

Sarah Leigh (Genomics England Curator)

Tag for-review tag was added to gene: SUZ12.

10 Dec 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: SUZ12 was added gene: SUZ12 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SUZ12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SUZ12 were set to 28229514; 30019515; 31736240; 15385962; 19535498; 31724824 Phenotypes for gene: SUZ12 were set to Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall Penetrance for gene: SUZ12 were set to unknown Review for gene: SUZ12 was set to GREEN