期刊
HUMAN MUTATION
卷 38, 期 6, 页码 611-614出版社
WILEY
DOI: 10.1002/humu.23211
关键词
ASAH1; next-generation sequencing; spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME); transcriptome sequencing
资金
- Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute
- Ontario Research Fund
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation [OGI-064]
- NIH [R01HG008150, R01MH101814, U01HG007436, T32HG000044, U01HG009080]
- National Science Foundation GRFP [DGE-114747]
- Stanford Center for Computational, Evolutionary, and Human Genomics (CEHG)
At least 15% of the disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in noncoding regions. Whole-transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease-relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p<10(-16)). Subsequent Sanger-sequencing identified the splice mutation responsible for the isoform (c.504A>C;p.Lys168Asn) and provided a molecular diagnosis of autosomal-recessive spinal muscular atrophy with progressive myoclonic epilepsy. Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for nonhematological conditions, providing a diagnosis for these otherwise unsolved patients.
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