The long-term goal of the project is to develop, validate and commercialize the first FDA-cleared IVD test kit for the rapid and differential diagnosis of Myotonic Dystrophy type 1 (DM1) and DM type 2 (DM2) using a unified and streamlined PCR/CE assay. DM1 and DM2 are the major categories of the most prevalent adult onset muscular dystrophies (DM). There is an urgent clinical need for an improved, cost-effective, and comprehensive DM test which enables early-stage, rapid diagnosis, and differentiation amongst the clinical disease categories of DM1 and DM2. DM diagnosis is frequently delayed because of late-onset clinical presentation of diverse symptoms, which often also overlap with other disorders, leading to late-, under- or misdiagnosis of patients. A readily accessible, yet highly sensitive and specific genetic test would be imperative for effective early or even pre-symptomatic diagnosis of the disease. DM1 is classified by a pathogenic expansion of more than 50 CTG repeats in the 3? UTR of the DMPK gene, and severity generally tracks with size. DM2 is characterized by an expansion of more than 75 CCTG repeats in exon 1 of CNBP, and bears a unique diagnostic challenge due to structural variation surrounding the CCTG repeat region, extremely large size (average 5000 and as large as 11000 repeats), and characteristic somatic mosaicism. Current DM testing requires multiple PCR methods to reliably amplify ~150 repeats and Southern Blot reflexing which is labor intensive and requires a considerable amount genomic DNA. The technical challenges that are distinct for each indication will be addressed, and 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 improved, high resolution genotyping. For DM1, the method will incorporate a new engineered enzyme for enhanced processivity to eliminate the need for reflex testing. For DM2, a multiplexing strategy will be employed and the workflow will be unified between both assays. Sophisticated bioinformatics analysis will be incorporated to identify expanded regions, provide visualization of fragment patterns and sizing of normal and mutant alleles. Advanced DM testing that provides standardized results across different laboratories offers important benefits to patients and families, as well as critical support for risk determination across populations, emerging therapies and clinical trials.
We are developing a molecular-based test for improved myotonic dystrophy testing which enables early- stage, rapid diagnosis, and differentiation amongst the different types of myotonic dystrophy. The test will be useful to standardized results across different laboratories, and to support clinical research studies to advance the field.
