in this patient, where mRNA degradation is predicted. Full homeostatic correction in the presence of NMD would favor the dominant-negative model, but leaves the clinical presentation of Patient 11 unexplained. A reduced ADNP expression in haploinsufficient samples would indicate that the mutant protein actively deregulates the feedback loop. Deregulation might be a consequence of the inability to harvest additional cofactors to the promoter region, while at the same time preventing wild-type protein to bind to the promoter binding site. Similarly, mutant ADNP might occupy alternative target sequences, while being unable to bind to HP1α or BAF. As such, despite the presence of functional BAF complexes, chromatin remodeling is hampered, leading to downstream alterations in gene expression patterns. To test this hypothesis, ChIP-seq and RNA-seq analysis of cell lines of the available patients could be useful.
