Remodelling the genetics of spinocerebellar entities : new genes, phenotypes, and transmission modes lead to new concepts

Hereditary cerebellar ataxias (HCA) and spastic paraplegias constitute both ends of the neurodegenerative spectrum of spinocerebellar entities (SCE). Theses diseases are marked by a pronounced heterogeneity, both clinically, with various additional neurological or extraneurological signs, and genetically. They can indeed follow all transmission modes, and mutations in a myriad of genes have been described. SCE is hence a group of diseases that benefit greatly from Next-Generation Sequencing technologies. This work reports both screenings of large cohorts of patients with either panel or whole exome sequencing, as well as family studies. The latter allowed us to describe new modes of transmission for genes previously involved in human pathology, with either similar protein dysfunction, or loss- versus gain-of-function. We also describe two new genes implicated in a form of autosomal dominant HCA (CACNA1A), and an autosomal recessive subtype of dystonia and cerebellar atrophy (TOR1AIP1). Our results are illustrative of the genetic remodelling underway in complex genetic diseases, with permanent questioning of genotype-phenotype correlations. We discuss the how and the why of molecular diagnosis in this new era of sequencing.