Whole-transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy.

TitleWhole-transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy.
Publication TypeJournal Article
Year of Publication2017
AuthorsKernohan, KD, Frésard, L, Zappala, Z, Hartley, T, Smith, KS, Wagner, J, Xu, H, McBride, A, Bourque, PR, Consortium, CRare Canad, Bennett, SAL, Dyment, DA, Boycott, KM, Montgomery, SB, Chardon, JWarman
JournalHum Mutat
Volume38
Issue6
Pagination611-614
Date Published2017 06
ISSN1098-1004
KeywordsAcid Ceramidase, Child, Preschool, Humans, Male, Muscular Atrophy, Spinal, Mutation, Myoclonic Epilepsies, Progressive, Pathology, Molecular, RNA Splicing, Sequence Analysis, DNA, Transcriptome
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(pC;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.

DOI10.1002/humu.23211
Alternate JournalHum. Mutat.
PubMed ID28251733
PubMed Central IDPMC5889109
Grant ListR01 HG008150 / HG / NHGRI NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
T32 HG000044 / HG / NHGRI NIH HHS / United States
U01 HG007436 / HG / NHGRI NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States