Identifying Genetic Modifiers of Disease Severity in Myotonic Dystrophy Type 1 - Project Summary/Abstract This mentored career development award proposal describes the applicant, training plan, research project, and transition-to-independence to prepare Dr. Samuel Carrell to be an independent, R01-funded physician-scientist focused on identifying genetic modifiers of myotonic dystrophy. Candidate: I am an Assistant Professor of Neurology at the Virginia Commonwealth University. I completed my PhD with Charles Thornton, MD and my post-doctoral work with Dr. Beverly Davidson, PhD studying experimental genetic therapies for myotonic dystrophy. I completed my neurology residency and neuromuscular fellowship at the University of Pennsylvania (2018 – 2024), and I see patients in the muscular dystrophy association (MDA) clinic. My long-term goal is to use clinical data and pre-clinical modeling to better understand myotonic dystrophy to develop novel biomarkers and treatments for my patients in the MDA clinic. Environment: My training will occur in the Center for Inherited Myology Research (CIMR) at the Virginia Commonwealth University (VCU). CIMR is a multidisciplinary, translational research program directed by my primary mentor, Dr. Nicholas Johnson, MD, Professor and the Vice Chair of Research of Neurology. Dr. Johnson also directs the Myotonic Dystrophy Clinical Research Network, which is a unique resource for this proposal, as the patient cohorts and global collaborations here are built out of this network of investigators. My co-mentors include, Dr. Darren Monckton, PhD, Professor of Human Genetics with 30 years leading a productive research lab studying the human genetics of microsatellite repeat disorders, and Dr. Jinze Liu, PhD Professor of biostatistics who leads the bioinformatics resource core at VCU. Research: Clinical variability is a hallmark feature of myotonic dystrophy type 1 (DM1). Muscle weakness in DM1 ranges from severe, congenital-onset hypotonia to mild disability in older age. DM1 is caused by an expanded CTG repeat in the DMPK gene, and one source of variability is the CTG repeat itself; however, this explains only ~60% of variance observed in age-of-onset. Given this discrepancy, I hypothesize that trans-acting genetic variants that impact the molecular cascade of DM1 act as modifiers of disease severity in DM1. To accomplish this, I will generate the largest-to-date DM1 cohort by combining data from six natural history studies and measure the CTG repeat lengths in all participants (~1600 patients). I will model the impact of the CTG repeat on age-of-onset and functional measures, and quantify the residual variability. I will then test the impact of genetic variants in select genes involved in the pathogenic cascade of DM1. Next, using a well-established biomarker of DM1, I have developed a disease-responsive reporter as a proxy for disease severity. Using this reporter, I propose a complementary [functional genomic] screen in DM1 iPSC-derived myoblasts to identify genes that modify disease severity.
