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

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. 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.