Whole‐transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy. Issue 6 (28th March 2017)

• Record Type: Journal Article
• Authors: Kernohan, Kristin D.; Frésard, Laure; Zappala, Zachary; Hartley, Taila; Smith, Kevin S.; Wagner, Justin; Xu, Hongbin; McBride, Arran; Bourque, Pierre R.; Consortium, Care4Rare Canada; Bennett, Steffany A. L.; Dyment, David A.; Boycott, Kym M.; Montgomery, Stephen B.; Warman Chardon, Jodi
• Is Part Of: Human mutation. Volume 38:Issue 6(2017)
• Page Start: 611
• Page End: 614
• Publication Date: 2017-03-28
• Subjects: ASAH1 -- next‐generation sequencing -- spinal muscular atrophy with progressive myoclonic epilepsy (SMA‐PME) -- transcriptome sequencing; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23211
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : At least 15% of disease mutations affect splicing, many of which will not be identified by current DNA testing. We describe an individual with atypical spinal muscular atrophy. Clinically‐based NGS sequencing identified a single pathogenic variant in ASAH1 . Genome‐wide RNA sequencing from blood identified an atypical ASAH1 isoform, and subsequent Sanger sequencing identified the second disease causing variant. Leveraging genome‐wide RNA‐based NGS, in addition to DNA NGS, is a comprehensive and unbiased method to diagnose rare neurological disease. Abstract: 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.