Automation of the genotyping process for the myotonic dystrophy type 1 CTG repeat locus using next generation sequencing. (360G-Wellcome-207148_Z_17_Z)

Myotonic dystrophy type 1 (DM1) is a severe inherited neurological disorder caused by an expansion of CTG repeats in the DMPK gene. More repeats cause more severe disease and an earlier age at onset. Genotyping of the DMPK CTG repeat is usually determined by fragment length analysis. The DMPK CTG repeat is not usually genotyped in standard next generation sequencing protocols due to a combination of problems with read length and mapping. We have solved most of these problems developing new methods for high-throughput sequencing of DMPK CTG repeat alleles. In this project we will develop an automated bioinformatic pipeline for genotyping repeat lengths at the DMPK locus by adapting a pipeline we have already developed for automated genotyping of the Huntington disease CAG repeat. Adapting the pipeline to automated genotyping of the DMPK locus will require optimisation of the trimming and alignment parameters and reprogramming in Python of the machine learning component used to automatically call the diploid genotypes from the read length distributions. This new method will facilitate research to investigate the causes of variability of myotonic dystrophy, lead to an improved diagnostic test, and to new methods for screening for this disorder in the general population.