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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.
Genomic and transcriptome sequencing identified a novel dystrophin gene (DMD) structural variant and a DIP2B CGG expansion in a patient with Duchenne muscular dystrophy (DMD) and intellectual disability, overcoming limitations of conventional genetic testing.
Area of Science:
- Genomics and transcriptomics
- Rare genetic disorders
- Molecular diagnostics
Background:
- Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene (DMD).
- Intellectual development disorders can be associated with CGG repeat expansions in genes like DIP2B.
- Conventional genetic testing often fails to identify complex structural variants or repeat expansions.
Purpose of the Study:
- To demonstrate the diagnostic utility of combining genomic short-read sequencing (SRS) and transcriptome sequencing.
- To identify novel genetic variants in a patient with Duchenne muscular dystrophy (DMD) and intellectual disability.
- To resolve complex genetic alterations that eluded standard diagnostic approaches.
Main Methods:
- Genomic short-read sequencing (SRS) was performed.
- Skeletal muscle transcriptome sequencing was utilized.
- Targeted programmable long-read sequencing (LRS) was employed for confirmation.
Main Results:
- A 216 kb paracentric inversion overlapping two DMD promoters was identified via SRS.
- Transcriptome analysis revealed significant underexpression of DMD and overexpression of DIP2B.
- A 109 CGG repeat expansion in the DIP2B 5' UTR was detected, confirmed as 270 repeats by LRS, which also validated the DMD structural variant.
Conclusions:
- Integrated transcriptome and genomic sequencing effectively resolved a complex DMD inversion and a DIP2B repeat expansion.
- This multi-omic approach enhances diagnostic yield for complex genetic disorders like DMD with co-occurring intellectual disability.
- Further longitudinal studies are warranted to elucidate the clinical significance of the identified DIP2B genotype.
