Fig. 5

Scores generated for different subjects by the ADNP classification model. A 3-class SVM classifier generates three scores (0–1) for every subject as the probability of having a DNA methylation profile similar to what is observed in epi-ADNP-1, epi-ADNP-2, or none of these. The Y-axis represents scores 0–1, generated for each of the three classes on the X-axis. Every point represents a single sample. Hollow points indicate the training samples and filled points indicate the testing samples. By default, the SVM classifier defines a cutoff of 0.5 for assigning the class; however, the vast majority of the tested individuals received a score < 0.2 or > 0.8. Therefore, to improve visualization, the points are jittered. The first two top panels show trials performed for known cases of epi-ADNP-1 and epi-ADNP-2, all of which were classified into the correct categories. The middle two panels illustrate trials performed on 2315 healthy individuals (left) and 780 patients with neurodevelopmental syndromes other than ADNP (right), all of which are scored low for both episignatures, but have received very high scores for the non-ADNP category. This latter group includes subjects diagnosed with imprinting defects (Angelman, Prader-Willi, Beckwith-Wiedemann, and Silver-Russell syndromes), non-syndromic autism spectrum disorders, BAFopathies (Coffin-Siris, Nicolaides-Baraitser, and Chr6q25 microdeletion syndromes), RASopathies, autosomal dominant cerebellar ataxia, deafness, and narcolepsy, ATRX, Coffin-Lowry, Cornelia de Lange, CHARGE, CHOPS, Claes-Jensen, Coffin-Lowry, Down, Dup7, Floating-Harbor, Fragile X, Genitopatellar, Juberg-Marsidi, Kabuki, Rett, Saethre-Chotzen, Sotos, Weaver, and Williams syndromes. The last two panels show trials performed for suspected and unresolved cases. Among the suspected cases (n = 7), who based on clinical or molecular assessments are ADNP candidates, one is classified as epi-ADNP-1 and one other as epi-ADNP-2. Unresolved subjects include 1150 undiagnosed patients with neurodevelopmental presentations, among which three have been classified as epi-ADNP-1