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Whole‐transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy
Author(s) -
Kernohan Kristin D.,
Frésard Laure,
Zappala Zachary,
Hartley Taila,
Smith Kevin S.,
Wagner Justin,
Xu Hongbin,
McBride Arran,
Bourque Pierre R.,
Consortium CareRare Canada,
Bennett Steffany A. L.,
Dyment David A.,
Boycott Kym M.,
Montgomery Stephen B.,
Warman Chardon Jodi
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23211
Subject(s) - biology , sanger sequencing , spinal muscular atrophy , exome sequencing , transcriptome , rna splicing , genetics , progressive myoclonus epilepsy , mutation , exon , bioinformatics , gene , rna , gene expression
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.