Mendelian neurodevelopmental disorders (NDDs) are collectively common yet individually caused by single mutated genes. With the increasing genetic diagnostic possibilities, a rapidly growing number of Mendelian syndromes are currently defined however mostly by somatic characteristics. Yet, in NDDs, the cognitive and psychiatric symptoms are often present and so far hardly studied, though these are often a huge burden for patients and their caregivers. Prior to the development of new NDD specific interventions, it is crucial to have a biological framework that fits to the neurocognitive profiles of each unique NDD. Given the rapidly rising number of mutated genes causing NDDs, there is a need for a template how to initiate reciprocal translational research for these disorders. By reciprocal we imply an integration of neurobiological findings in the clinical practice and vice versa. Our general aim is to enhance the development and implementation of novel intervention strategies for Mendelian syndromes by obtaining fundamental insights in both the clinical and biological consequences of mutated genes causing these disorders. As proof-of-principle we (1) intent to follow up on our identification of patients with SIN3A mutations (Witteveen-Kolk Syndrome) and characterize their cognitive and neuropsychiatric profiles in detail. Also, we will (2) study the role of SIN3A in human PFC corticogenesis in patient-derived cortical/cerebral organoids, thus providing insight in the effect of such mutations on human brain development, (3) cross-validate cortical network development in an in utero electroporation mouse model and finally (4) define intervention strategies for the clinical setting. Our proposal clearly asks for a multidisciplinary collaboration between experts in genetics, brain neurodevelopment, neurocognition and psychiatry. Results of our project will not only lead to important fundamental insights in genetic defects underlying mental disorders, but also to improvements in the treatment of patients with NDDs.
