Next Generation Sequencing (NGS) technologies have resulted in the accumulation of a large amount of genetic causes for Mendelian diseases, with often no clear-cut link or evident cellular function correlating to the phenotype available. Conversely, a multitude of patients with Rare Diseases, of which many suffer from neuropathies, are lacking a genetic etiology. SPTAN1 (?-II-spectrin) provides an excellent example of this, with a notably high phenotypical heterogeneity but surprisingly little known about its molecular biology and cellular functions. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). Furthermore, our own unpublished data show patients with ataxia and Hereditary Spastic Paraplegia (HSP), widening the phenotypical spectrum even further. I set out to uncover the molecular causes of the phenotypical heterogeneity present in SPTAN1, starting with the curation of an extensive database of SPTAN1 mutations and their associated phenotypes. Leveraging the information contained in this database through the use of machine learning techniques, I will perform experiments in carefully chosen patient-derived induced Pluripotent Stem Cells (iPSCs) that will allow the uncovering of differential effects between variants in SPTAN1 and their associated phenotypes, yield novel candidate genes for such disorders and teach us about the patho-biology of spectrins.