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Transcriptome and Genome Analysis Uncovers a DMD Structural Variant: A Case Report
Chiara Folland1, Vijay Ganesh1, Ben Weisburd1
1Centre for Medical Research, University of Western Australia (C.F., G.R.), Harry Perkins Institute of Medical Research, Perth, Australia; Center for Mendelian Genomics (V.G., B.W., A.O.-L., H.L.R.), Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Neurology (V.G.), Brigham and Women's Hospital; Division of Genetics and Genomics (V.G., A.O.-L.), Boston Children's Hospital, MA; Department of Anatomical Pathology (C.M., P.K.), Alfred Health; Department of Medicine (C.M., P.K.), Central Clinical School, Monash University, Melbourne; Murdoch Children's Research Institute (A.J.K.); Department of Neurology (A.J.K.), Royal Children's Hospital; Department of Paediatrics (A.J.K.), University of Melbourne, Victoria, Australia; Center for Genomic Medicine (A.O.-L., H.L.R.), Massachusetts General Hospital, Boston, MA; Genomics Pillar (I.S., S.R.C., I.W.D.), Garvan Institute of Medical Research, Sydney, Australia; Centre for Population Genomics (I.S., S.R.C., I.W.D.), Garvan Institute of Medical Research and Murdoch Children's Research Institute, Australia; School of Clinical Medicine (S.R.C., I.W.D.), Faculty of Medicine and Health, UNSW Sydney, Australia; and School of Biomedical Sciences (G.R.), University of Western Australia, Perth, Australia.
Objective:
Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene (DMD). Hypermethylated CGG expansions within DIP2B 5' UTR are associated with an intellectual development disorder. Here, we demonstrate the diagnostic utility of genomic short-read sequencing (SRS) and transcriptome sequencing to identify a novel DMD structural variant (SV) and a DIP2B CGG expansion in a patient with DMD for whom conventional diagnostic testing failed to yield a genetic diagnosis.
Methods:
We performed genomic SRS, skeletal muscle transcriptome sequencing, and targeted programmable long-read sequencing (LRS).
Results:
The proband had a typical DMD clinical presentation, autism spectrum disorder (ASD), and dystrophinopathy on muscle biopsy. Transcriptome analysis identified 6 aberrantly expressed genes; DMD and DIP2B were the strongest underexpression and overexpression outliers, respectively. Genomic SRS identified a 216 kb paracentric inversion (NC_000023.11: g.33162217-33378800) overlapping 2 DMD promoters. ExpansionHunter indicated an expansion of 109 CGG repeats within the 5' UTR of DIP2B. Targeted genomic LRS confirmed the SV and genotyped the DIP2B repeat expansion as 270 CGG repeats.
Discussion:
Here, transcriptome data heavily guided genomic analysis to resolve a complex DMD inversion and a DIP2B repeat expansion. Longitudinal follow-up will be important for clarifying the clinical significance of the DIP2B genotype.
