Development of a unified information-rich test for CNBP and DMPK to improve assessment of Myotonic Dystrophy Type 1 and 2

Project SummaryThe long term goal of the project is to developvalidate and commercialize the first FDA cleared IVD test kit for the rapid and differential diagnosis of Myotonic Dystrophy typeDMand DM typeDMusing a unified and streamlined PCR CE assayDMand DMare the major categories of the most prevalent adult onset muscular dystrophiesDMThere is an urgent clinical need for an improvedcost effectiveand comprehensive DM test which enables early stagerapid diagnosisand differentiation amongst the clinical disease categories of DMand DMDM diagnosis is frequently delayed because of late onset clinical presentation of diverse symptomswhich often also overlap with other disordersleading to lateunderor misdiagnosis of patientsA readily accessibleyet highly sensitive and specific genetic test would be imperative for effective early or even pre symptomatic diagnosis of the diseaseDMis classified by a pathogenic expansion of more thanCTG repeats in theUTR of the DMPK geneand severity generally tracks with sizeDMis characterized by an expansion of more thanCCTG repeats in exonof CNBPand bears a unique diagnostic challenge due to structural variation surrounding the CCTG repeat regionextremely large sizeaverageand as large asrepeatsand characteristic somatic mosaicismCurrent DM testing requires multiple PCR methods to reliably amplifyrepeats and Southern Blot reflexing which is labor intensive and requires a considerable amount genomic DNAThe technical challenges that are distinct for each indication will be addressedand the analysis will be combined into a single multiplexed test with a common reagent system and workflow to achieve a unified readout on a sizing platform across each of the clinical categories for improvedhigh resolution genotypingFor DMthe method will incorporate a new engineered enzyme for enhanced processivity to eliminate the need for reflex testingFor DMa multiplexing strategy will be employed and the workflow will be unified between both assaysSophisticated bioinformatics analysis will be incorporated to identify expanded regionsprovide visualization of fragment patterns and sizing of normal and mutant allelesAdvanced DM testing that provides standardized results across different laboratories offers important benefits to patients and familiesas well as critical support for risk determination across populationsemerging therapies and clinical trialsProject NarrativeWe are developing a molecular based test for improved myotonic dystrophy testing which enables earlystagerapid diagnosisand differentiation amongst the different types of myotonic dystrophyThe test will be useful to standardized results across different laboratoriesand to support clinical research studies to advance the field