RNAseq analysis for the diagnosis of muscular dystrophy
Hernan Gonorazky, Minggao Liang, Beryl Cummings, Monkol Lek, Johann Micallef, Cynthia Hawkins, Raveen Basran, Ronald Cohn, Michael D Wilson, Daniel MacArthur, Christian R Marshall, Peter N Ray, James J Dowling, Hernan Gonorazky, Minggao Liang, Beryl Cummings, Monkol Lek, Johann Micallef, Cynthia Hawkins, Raveen Basran, Ronald Cohn, Michael D Wilson, Daniel MacArthur, Christian R Marshall, Peter N Ray, James J Dowling
Abstract
The precise genetic cause remains elusive in nearly 50% of patients with presumed neurogenetic disease, representing a significant barrier for clinical care. This is despite significant advances in clinical genetic diagnostics, including the application of whole-exome sequencing and next-generation sequencing-based gene panels. In this study, we identify a deep intronic mutation in the DMD gene in a patient with muscular dystrophy using both conventional and RNAseq-based transcriptome analyses. The implications of our data are that noncoding mutations likely comprise an important source of unresolved genetic disease and that RNAseq is a powerful platform for detecting such mutations.
Figures
References
- Landfeldt E, Lindgren P, Bell CF, et al. The burden of Duchenne muscular dystrophy: an international, cross‐sectional study. Neurology 2014;83:529–536.
- Lopez‐Bastida J, Oliva‐Moreno J. Cost of illness and economic evaluation in rare diseases. Adv Exp Med Biol 2010;686:273–282.
- Chelly J, Desguerre I. Progressive muscular dystrophies. Handb Clin Neurol 2013;113:1343–1366.
- Ankala A, da Silva C, Gualandi F, et al. A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield. Ann Neurol 2015;77:206–214.
- Wong SH, McClaren BJ, Archibald AD, et al. A mixed methods study of age at diagnosis and diagnostic odyssey for Duchenne muscular dystrophy. Eur J Hum Genet 2015;1294–300.
- Jiang T, Tan MS, Tan L, Yu JT. Application of next‐generation sequencing technologies in Neurology. Ann Transl Med 2014;2:125.
- Yang Y, Muzny DM, Reid JG, et al. Clinical whole‐exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013;369:1502–1511.
- Baskin B, Banwell B, Khater RA, et al. Becker muscular dystrophy caused by an intronic mutation reducing the efficiency of the splice donor site of intron 26 of the dystrophin gene. Neuromuscul Disord 2009;19:189–192.
- Ruggieri A, Ramachandran N, Wang P, et al. Non‐coding VMA21 deletions cause X‐linked myopathy with excessive autophagy. Neuromuscul Disord 2015;25:207–211.
- Trabelsi M, Beugnet C, Deburgrave N, et al. When a mid‐intronic variation of DMD gene creates an ESE site. Neuromuscul Disord 2014;24:1111–1117.
- Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9:77–93.
- Irimia M, Weatheritt RJ, Ellis JD, et al. A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 2014;159:1511–1523.
- Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA‐seq aligner. Bioinformatics 2013;29:15–21.
- Harrow J, Frankish A, Gonzalez JM, et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res 2012;22:1760–1774.
- Trapnell C, Hendrickson DG, Sauvageau M, et al. Differential analysis of gene regulation at transcript resolution with RNA‐seq. Nat Biotechnol 2013;31:46–53.
- Kevelam SH, Taube JR, van Spaendonk RM, et al. Altered PLP1 splicing causes hypomyelination of early myelinating structures. Ann Clin Transl Neurol 2015;2:648–661.
- Ku CS, Wu M, Cooper DN, et al. Exome versus transcriptome sequencing in identifying coding region variants. Expert Rev Mol Diagn 2012;12:241–251.
- Waddell LB, Monnier N, Cooper ST, et al. Using complementary DNA from MyoD‐transduced fibroblasts to sequence large muscle genes. Muscle Nerve 2011;44:280–282.
- Tsunemoto RK, Eade KT, Blanchard JW, Baldwin KK. Forward engineering neuronal diversity using direct reprogramming. EMBO J 2015;34:1445–1455.
- Bellin M, Marchetto MC, Gage FH, Mummery CL. Induced pluripotent stem cells: the new patient? Nat Rev Mol Cell Biol 2012;13:713–726.
Source: PubMed