ADNP syndrome, also known as Helsmoortel-van Der Aa syndrome, is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. ADNP syndrome is caused by mutations in the activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with ADNP syndrome, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with ADNP syndrome into two groups, based on the location of the mutations. Here, we conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two, mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome. We found limited phenotypic differences between the two ADNP groups, and no evidence that individuals with more widespread methylation changes are more severely affected. Also, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with ADNP syndrome. Our data warrant caution in harnessing methylation signatures in ADNP syndrome as a tool for clinical stratification, at least with regards to behavioral phenotypes.

Episignatures stratifying ADNP syndrome show modest correlation with phenotype