Contribution of Gene Mutations to OGID
Using exome or targeted gene analyses, we identified a pathogenic mutation in one of 14 genes in 357 individuals with OGID, giving a diagnostic yield of 50% (Figure 1). By far the most common cause was a mutation in NSD1 (240 cases, 34%), followed by EZH2 (34, 4.8%), DNMT3A (18, 2.5%), PTEN (MIM: 601728) (16, 2.3%), NFIX (MIM: 164005) (14, 2.0%), CHD8 (MIM: 610528) (12, 1.7%), BRWD3 (MIM: 300553) (7, 1.0%), HIST1H1E (5, 0.7%), PPP2R5D (3, 0.4%), (2 cases each) EED (MIM: 605984), GPC3 (MIM: 300037), and MTOR (MIM: 601231), and (1 case each) AKT3 (MIM: 611223) and PIK3CA (MIM: 171834) (Table S1). Among the 323 parent-proband trios, we identified a cause in 191 (59%) of which 179 were de novo mutations and 12 were inherited.
Our data allow confirmation that EED mutations cause OGID. Two case reports of individuals with a characteristic phenotype that includes overgrowth have been published.10, 27 We here present two additional cases with a de novo EED mutation. The individuals have the same facial phenotype to each other and to previously reported case subjects, with long, narrow palpebral fissures, telecanthus, and retrognathia. Notably, EED is a direct binding partner of EZH2,28 which has an established role in causing OGID.29 Some role in overgrowth was either known, or has been proposed, for the remainder of these, apart from HIST1H1E (see GeneReviews by Eng in Web Resources).6, 9, 10, 12, 29, 30, 31, 32, 33, 34, 35