Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis.