Mutations in EZH2 cause Weaver syndrome

Abstract

We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.

Figure 1

Proband from Weaver et al. and Two Additional Probands Described in This Study Proband 1 is shown at 18 months (A), 6 years (B), 11 years (C), 17 years (D), 21 years (E), and 30 years (F, G, and H). Proband 2 is shown at age 7 years (I) and 13 years (J, K, and L). Proband 3 is shown at birth (M), 12 months (N), 24 months (O), 42 months (P), 6 years (Q), 10 years (R), 11 years (S), 16 years (T), and 19 years (U and V). Proband 3 at 8 years in a stance that shows elbow and knee contractures (W). Photos are published with the proxy consent of the parents and assent of the probands.

Figure 2

Sanger Confirmation of Sequence Variants (A) The c.457_459del mutation in Proband 1 (curly bracket) is de novo. (B) The c.2080C>T mutation in Proband 2 (arrow) is de novo. (C) The c.394C>T mutation in Proband 3 (arrow) is de novo.

Figure 3

Schematic of Human EZH2 Coding exons are indicated by rectangles and noncoding exons by open rectangles. The exons are numbered starting from the exon containing the 5′ untranslated region (UTR). The putative SANT DNA-binding domain is shown in orange, the SET domain in blue, and the WD-binding domain in green. The SMART or Pfam domain identifier is presented in parentheses. Exons with no InterPro annotation are indicated in gray.

Figure 4

Ribbon Model of the EZH2 SET Domain The wild-type histidine residue is shown in blue and the bulkier tyrosine in white and red. The nearby binding site of the S-Adenosylmethionine cofactor is also indicated.