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

Background: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. Results: 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. Conclusions: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis. Keywords: Accelerated aging; Chromatin remodeling; DNA methylation; Episignature; HIST1H1E; Intellectual disability; Rahman syndrome; Replicative senescence.