Characterization of the genetic architecture of neurodevelopmental disorders using Duchenne Muscular Dystrophy as a model

Abstract

Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disease caused by loss of function mutations in the DMD gene. In addition to the muscle phenotype, about 30% of patients manifest different Neurodevelopmental Diseases (NDDs), which occur 15-30 times more often than in the general population. Although loss of function of the smaller isoforms of DMD (Dp140 and Dp71) partly explain the increased risk for intellectual disability, the molecular mechanisms associated with the manifestation of different NDDs, such as autism, and intellectual disability itself in patients with DMD are not yet fully understood. Different studies have shown the relevance of rare variants of moderate effect in the genetic background for the manifestation and variability of NDDs, compatible with an oligogenic inheritance model. Thus, the objective of this project is to verify if mutations in DMD associated with an accumulation of rare variants of moderate effect on neurodevelopmental genes are responsible for the development of different NDD in DMD patients. To this end, the exome of 100 patients diagnosed with DMD (half of them with NDD and half not) will be sequenced and analyzed for the number of potentially pathogenic variants in known or candidate neurodevelopmental genes. The data found in both subgroups will then be analyzed to determine if there is an enrichment of potentially pathogenic variants in neurodevelopmental genes in patients with DMD associated with NDD. Functional studies will be designed to evaluate the effect of combining the variant in DMD with other variants in genes selected in the genomic study. (AU)