GSE126342
Effect of the CTG repeat expansion on RNA splicing in children with congenital myotonic dystrophy
Congenital myotonic dystrophy (CDM) is the most severe form of myotonic dystrophy type-1 (DM1).  In adult DM1, dysregulation of alternative splicing of many transcripts results in the disease pathology.  In CDM, the degree of aberrant splicing is not known, nor is it understood which transcripts are altered.  Muscle biopsies were obtained from children with CDM, adults with DM1, healthy adult controls, and pathologically normal pediatric muscle.  RNA was isolated and paired-end RNA-Seq was performed.  Analysis used MAJIQ to generate percent spliced in (PSI) values.  Sample sets were analyzed with Weighted Gene Co-expression Network Analysis (WGCNA) to identify splicing patterns. 11 muscle biopsies from children with CDM (age 2 month-16 years), 9 pediatric controls (age 1 month-13 years), 16 adult DM1 patients (ages 29-57), and 6 adult healthy controls (ages 19-28) were used for analysis.  MAJIQ identified 2266 splicing events with adequate read depth and a PSI>0.15.  WGCNA identified 4 patterns of splicing.  The majority of the splicing events were the same in cases of CDM and DM1, while a subset of splicing changes were unique to CDM, many (e.g., PALLD) specific to development.  The relative expression of RNA splicing factors with age may account for differences in the splicing patterns in CDM and DM1.  Children with CDM have the RNA splicing events previously identified in adults with DM1, despite a divergent phenotype.  There are also a minority of splicing events that are specific to CDM, largely related to transcripts regulating development. Overall design: 42 skeletal muscle biopsy samples: 11 congenital myotonic dystrophy (CDM), 16 adult myotonic dystrophy, 9 pediatric controls, 6 adult controls