These observations are compatible with a dominant negative mutational mechanism. A dominant negative model is also in line with a discordance in over- or underexpression in our patients versus the results in mice/P19 cells for several genes, but p53 and ADNP2 [Vulih-Shultzman et al., 2007; Helsmoortel et al., 2014b]. However, since the initial report on 10 patients, an 11th patient has been identified with a stop mutation in the fourth exon, which is unlikely to escape nonsense mediated decay. Since the clinical presentation of this patient is not different from that of patients with a mutation in exon five, it challenges the dominant negative hypothesis as the only mutational mechanism. It would be interesting to investigate whether the homeostatic correction of ADNP mRNA levels observed in the initial patients with mutations in exon five, escaping nonsense mediated decay, is present 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
