Fig. 2

Two distinct and partially contrasting episignatures in ADNP syndrome. Separate analyses for the two identified clusters in ADNP-1 and ADNP-2 episignatures identified a larger number of probes for each group, indicating that the primary analysis had concealed the full spectrum of the methylation profiles of ADNP syndrome. Blue, red, and green (in points and panes) represent epi-ADNP-1, epi-ADNP-2, and control subjects, respectively. Using multiple dimensional scaling and hierarchical clustering analyses, it is shown that epi-ADNP-1 is associated with a mainly hypomethylated episignature (a, b). Probes associated with ADNP-1 episignature also separate epi-ADNP-2 subjects from controls, but with a milder opposite pattern of DNA methylation change (a, b). Similar observations are noted for epi-ADNP-2 specific probes (c, d), as well as the intersection of the two episignatures (e, f). The shared component (e, f) generates the most contrasting pattern between the two subtypes. Among the epi-ADNP-2 samples, a subject with a mutation in the most extreme end of the ADNP-2 region (c.2340T>G) shows the mildest changes of all (black arrows)