Deep phenotyping in brain malformations: from disease trajectories to the development of new networks of rare neuropediatric diseases

Deep phenotyping is pivotal in the study of rare neuropediatric diseases, as it enables a precise and comprehensive characterization of clinical features and improves disease understanding. Subjects with rare neuropediatric diseases exhibit unique and highly heterogeneous functioning, and therefore require individualized interventions, updated outcome evaluation, and adapted tools. By leveraging advanced imaging, detailed neuropsychological assessments, and integrative bioinformatics, deep phenotyping may serve as a link to specific genotypes, enhancing diagnostic accuracy and promoting the discovery of disease mechanisms and therapeutic targets. On the premise that current research in the field of rare neuropediatric diseases should not overlook deep phenotyping, my PhD program was structured around the development of an innovative tool for deep phenotyping and the characterization of neuroradiological and behavioral patterns associated with specific brain malformations. Grounded in a constant interplay between clinical care and research, the development of an innovative registry for diagnosed and undiagnosed rare neuropediatric diseases was undertaken within the framework of a multicenter network project. Chapter II outlines the development process, the structure of the platform, and its underlying philosophy. Chapter III presents all the studies conducted, focusing on the deep phenotyping of midline and posterior cranial fossa malformations. Regarding the former, biological pathways leading to septo-optic dysplasia were analyzed, and both subjective and objective assessments of sleep were performed in patients with septo-optic dysplasia and corpus callosum agenesis. Concerning the latter, abnormal fetal neuroradiological findings are correlated with long-term clinical outcomes, and the phenotypic patterns of posterior cranial fossa malformations are described and linked to both clinical prognosis and genotype.