Weaver Syndrome via the EZH2 Gene

Weaver syndrome (OMIM 277590) is an overgrowth disorder characterized by tall stature, advanced bone age, macrocephaly, dysmorphic facies, and variable learning disability (Weaver et al. J Pediat 84(4):547-552, 1974; Gibson et al. Am J Hum Genet 90(1):110-118, 2012). Facial features include hypertelorism, large bifrontal diameter, flat occiput, large ears, long philtrum, and retrognathia. Overgrowth is of prenatal onset. Other findings reported include prominent digit pads, thin deep-set nails, umbilical hernia, and scoliosis. Sotos syndrome (OMIM 117550) is an overgrowth disorder with many overlapping features with Weaver syndrome (Opitz et al. Am J Med Genet 79(4):294-304, 1998). A clinical finding that distinguishes Weaver syndrome from Sotos syndrome is retrognathia with a prominent chin crease (Gibson et al., 2012). Conversely, congenital heart disease, renal anomalies, and seizures are more common in Sotos syndrome (Tatton-Brown and Rahman. Am J Med Genet C Semin Med Genet 163(2):86-91, 2013). Although somatic mutations of the EZH2 gene are documented in lymphoid and myeloid malignancies (Ernst et al. Nat Genet 42(8):722-726, 2010; Chase et al. Clin Cancer Res 17(9):2613-2618, 2011, Morin et al. Nat Genet 42(2):181-185, 2010; Nikoloski et al. Nat Genet 42(8):665-667, 2010), cases of Weaver syndrome with constitutional EZH2 mutations and cancer appear to be rare (Tatton-Brown et al. Oncotarget 2(12):1127-1133, 2011).

Weaver syndrome due to EZH2 mutations is an autosomal dominant disorder. The majority of pathogenic EZH2 variants are amino acid substitutions and, unlike the NSD1 gene and Sotos syndrome, few truncating mutations have been reported (Tatton-Brown et al., 2011). Mutations are de novo in nearly all cases (Gibson et al., 2012 and Tatton-Brown et al., 2011).

EZH2 (OMIM 601573) encodes a histone methyltransferase and, like NSD1, is a SET domain protein that regulates transcription.

Analytical sensitivity should be high because all reported EZH2 mutations are expected to be detectable with bi-directional DNA sequencing. Clinical sensitivity is difficult to predict due to the overlapping features with Sotos syndrome. However, with careful phenotypic ascertainment, sensitivity may be high (Tatton-Brown et al. Oncotarget 2(12):1127-1133. 2011).

Thus far, no gross deletions or duplications have been reported in EZH2 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the EZH2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).