SUZ12 – Weaver syndrome

Pathogenic heterozygous variants in SUZ12 (HGNC:17101) have been implicated in Weaver syndrome (MONDO:0010193), an autosomal dominant overgrowth disorder characterized by accelerated skeletal maturation, macrocephaly, characteristic facial features, and variable neurodevelopmental outcomes. Initial reports identified a single mosaic SUZ12 missense variant in a Weaver-like proband, and subsequent case series consolidated evidence across multiple cohorts, firmly establishing SUZ12 as a causative gene for Weaver syndrome.

Genetic evidence includes 13 unrelated probands harboring rare SUZ12 variants across three studies: ten patients with four frameshift, two missense, one nonsense, and two splice site variants (n=10) (PMID:31736240), two individuals with a missense (c.1797A>C (p.Gln599His)) and a frameshift variant (n=2) (PMID:30019515), and one proband with a heterozygous c.1829A>T (p.Glu610Val) variant inherited from a mosaic parent (n=1) (PMID:28229514). Familial transmission, including a mosaic father, provides segregation support (affected_relatives=1) (PMID:28229514).

The SUZ12 variant spectrum spans loss-of-function and missense classes. Total variants include five frameshift, three missense, one nonsense, and three splice site alterations. A representative missense mutation is c.1807T>C (p.Phe603Leu), observed de novo in a patient with classic Weaver features.

Functional assays demonstrate that SUZ12 missense variants impair PRC2 histone methyltransferase activity, leading to reduced H3K27 trimethylation in vitro (PMID:28229514). Mouse Suz12-null embryos display loss of di- and tri-methylated H3K27 and early embryonic lethality, underscoring haploinsufficiency as the mechanism of pathogenicity (PMID:15385962).

Clinically, affected individuals present with prenatal and postnatal overgrowth, macrocephaly, advanced bone age, round facies, large ears, horizontal chin crease, skeletal anomalies, and developmental delay/intellectual disability (HP:0001249). Some patients exhibit genitourinary anomalies (HP:0000119) and neuroimaging abnormalities, reflecting variable expressivity.

No studies to date have refuted the association between SUZ12 variants and Weaver syndrome. The consistency of de novo occurrences, familial segregation, and concordant functional data support a robust gene-disease link.

Integration of genetic and experimental data confirms that heterozygous SUZ12 variants cause Weaver syndrome via PRC2 haploinsufficiency. Diagnostic sequencing of SUZ12 should be considered in patients with unexplained overgrowth and characteristic facial and skeletal features. Key take-home: SUZ12 testing enables precise diagnosis and genetic counseling for Weaver syndrome.

References

• American Journal of Medical Genetics Part C • 2019 • Rare SUZ12 variants commonly cause an overgrowth phenotype. PMID:31736240
• Clinical Genetics • 2018 • Novel SUZ12 mutations in Weaver-like syndrome. PMID:30019515
• Human Mutation • 2017 • Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. PMID:28229514
• The EMBO Journal • 2004 • Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. PMID:15385962

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