Special thanks to the Testa Lab people who shared this journey with me: Marlene Pereira, @sebastianotrattaro.bsky.social, @michelegabriele.bsky.social, Francesco Dossena, Erika Tenderini and the whole amazing group of people I've been so fortunate to work with.

Thanks to Giuseppe and Raymond for bringing together such an enthusiastic and international team to work on this project, and for the smooth collaboration.

GRNs computed from multiome profiling in HVDAS cortical organoids prioritize key AKG-bound TFs targets whose in silico KO rescues the accelerated maturation phenotype.

Patient-derived cortical organoids harboring HVDAS-causing ADNP mutations show morphological and functional impairments such as smaller-sized organoids, and reduced mitotic capacity of neuronal progenitors coupled with accelerated neuronal differentiation.

ADNP DNA-binding motif in iPSCs and hNSCs differs from the one of CTCF, as previously reported in mESCs. MS and co-IP show that in humans ADNP interacts with GTF2I and KDM1A forming the "AKG" complex. Plus, ADNP KO in hNSCs show derepression of KDM1A-bound promoters.

Patient-derived iPSCs show decreased genome-wide ADNP occupancy, prevalently leading to gene activation at ADNP-lost sites. Moreover, ADNP represses its targets through regulatory regions rich in primate-specific transposable elements (TEs).

We modelled ADNP across iPSCs, neural stem cells, neural crest stem cells, and cortical organoids, integrating patient-derived models with endogenous gene editing.