We present here data showing that certain HIST1H1E mutations cause OGID. Through exome sequencing we identified five unrelated probands—COG0405, COG0412, COG0552, COG1739, and COG1832—with heterozygous HIST1H1E protein truncating variants (PTVs) (Figure 2, Tables 1 and S1). In four probands the PTV had arisen de novo. Parental samples were not available for the fifth child, but she carried the same mutation as one of the children with a de novo mutation. The detection of four de novo HIST1H1E mutations in 710 individuals is highly unlikely to have occurred by chance, as determined from gene-specific de novo mutation rates (p = 5.17 × 10−15). None of the mutations are present in the ExAC dataset, nor in 11,677 exomes analyzed in-house with similar pipelines. These results strongly support HIST1H1E mutations as a cause of OGID.