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

Hum Mutat. 2017 Jun;38(6):611-614. doi: 10.1002/humu.23211. Epub 2017 Mar 28.


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.

Keywords: ASAH1; next-generation sequencing; spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME); transcriptome sequencing.

Publication types

  • Case Reports
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Ceramidase / blood
  • Acid Ceramidase / genetics*
  • Child, Preschool
  • Humans
  • Male
  • Muscular Atrophy, Spinal / blood*
  • Muscular Atrophy, Spinal / complications
  • Muscular Atrophy, Spinal / genetics
  • Mutation
  • Myoclonic Epilepsies, Progressive / blood*
  • Myoclonic Epilepsies, Progressive / complications
  • Myoclonic Epilepsies, Progressive / genetics
  • Pathology, Molecular
  • RNA Splicing / genetics*
  • Sequence Analysis, DNA
  • Transcriptome / genetics


  • ASAH1 protein, human
  • Acid Ceramidase