Author(s): Nicholas Johnson, MD, Virginia Commonwealth University; Melissa Hale, PhD, Virginia Commonwealth University; Kameron Bates, MS, Virginia Commonwealth University; Nicholas Johnson, MD, Virginia Commonwealth University //

ABSTRACT: Research Objective: To identify genetic modifiers of DM1 in a large cohort of myotonic dystrophy type 1.    Background: Myotonic dystrophy type 1 is caused by a CTG repeat in the 3’UTR of the DMPK gene.  Genome-wide association studies (GWAS) have recently identified common trans-acting variants that associate with age of onset for Huntington disease (HD).  HD, like DM1, also results from germline and somatic expansion of CAG:CTG repeats, and it appears that the major trans-modifiers of HD act mainly at the level of somatic instability of repeats.  DM1 may be subject to similar influences and previous investigators have used a candidate gene approach in small DM1 cohorts; these studies reported nominal associations with common SNPs in DNA repair genes.    Methods: We will perform a GWAS in 700 individuals with DM1.  A PCR based method will determine length of the CTG repeat and test for CGG or CCG interruptions within the repeat tract.  We will use age of onset as the primary phenotype, incorporating a statistical model to control for the effects of repeat length.  Secondary phenotypes will include mean change on 10-meter walk (to assess the trajectory of motor function decline), grip strength, video hand opening time, and pulmonary or cardiac complications.  On all samples, whole exome genotyping will be performed with Illumina Omni2.5-Exome SNP arrays providing comprehensive coverage with ~2.5 million common, rare and exonic SNP variants.  Results: In a smaller cohort of 10 mothers with small CTG repeat expansions and children with very large repeat expansions, whole exome sequencing was performed.  Within this cohort, early results have identified a rare variant in MSH3 that may affect CTG repeat stability.  In the larger cohort, we have enrolled 255 participants with DM1 and performed CTG repeat sizing as well as collecting the age of onset.  Enrollment of the full cohort is ongoing.    Conclusions: Completion of this proposal may identify cis- and trans-acting genetic variants that lead to phenotypic variation in DM1, thereby providing new mechanistic insights and novel therapeutic targets.

Source of Funding: None