Computational Analysis of Regulatory Mutations in Developmental Disorders (360G-Wellcome-105368_Z_14_Z)

Only one third of patients with severe developmental disorders, including neurodevelopmental disabilities, can currently be diagnosed with causative mutations within protein coding sequences. Non-coding mutations that disrupt normal gene expression in critical developmental genes likely explain a proportion of the undiagnosed patients. The focus of this PhD project will be the integration of sequence data from the Deciphering Developmental Disorders (DDD) project and the 100,000 Genomes project with annotations of regulatory function to better understand the role of regulatory elements in development. This computational analysis will generate hypotheses relating to specific variants in individual genomic functional elements and these hypotheses will be validated by a combination of molecular profiling of accessible tissues from relevant patients, genetic replication of association in additional patients with similar phenotypes, and modelling in mice of putative pathogenic mutations.