Fig. 1

Correlation between the genetic coordinates of the ADNP mutations and two ADNP episignatures. Comparison of patients with ADNP syndrome and controls identified 1320 differentially methylated CpG sites. a Illustration of the top two dimensions of the multiple dimensional scaling of the patients (purple) and controls (green) using these probes reveals that while patients are separated from controls, they are clustered in two groups (indicated with dashed circles) with greater distances from each other than from controls. b A hierarchical clustering generates a similar pattern in which 11 ADNP cases generate one distinct cluster mainly representing hypomethylation events (epi-ADNP-1, blue-dashed rectangle), and the other 11 subjects generate a cluster different from both controls and the first cluster (epi-ADNP-2, red-dashed rectangle), showing a slightly hypermethylated pattern relative to controls. Notably, methylation changes in epi-ADNP-1 are more prominant than those in epi-ADNP-2. The top pane in the heatmap indicates the phenotype. Green, controls; purple, epi-ADNP syndrome. The heatmap color scale from blue to red represents the range of the methylation levels (beta values) between 0 and 1. c Evaluation of the genetic coordinates of the mutations reveals that, with the exception of one, all epi-ADNP-1 subjects have a mutation upstream c.1300, and all epi-ADNP-2 cases have mutations occurring between c.2000 and c.2340. The only exception is found for one epi-ADNP-1 patient having a mutation after c.2400. d A schematic representation of the mutations across the ADNP protein is presented in the bottom of the figure. Blue and red indicate the protein coordinates of the mutations related with ADNP-1 and ADNP-2 episignatures, respectively. Domains outside these two had no mutations in our cohort