The CTD of linker histones regulate higher-order chromatin structure through neutralization of negatively charged linker DNA.36 The pathogenic HIST1H1E mutations all result in the same shift in the reading frame and are predicted to generate similar truncated proteins, with a reduced net charge of 7–9 (compared to 44 for the wild-type protein) (Figure 2A). The mutant protein is thus likely to be less effective in neutralizing negatively charged linker DNA. Moreover, the truncation of the C-terminus likely impedes DNA binding and protein-protein interactions. It is also noteworthy that the other possible alteration in reading frame would reduce neither the net charge nor the length of the protein (Figure 2A). Taken together, these data suggest that specific HIST1H1E mutations, restricted in position and type, cause human overgrowth.