Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

Hum Mutat. 2018 Sep;39(9):1284-1298. doi: 10.1002/humu.23560. Epub 2018 Jul 25.


Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate.

Keywords: gene panel; high-throughput screening; non-5q spinal muscular atrophy; spinal muscular atrophy; targeted sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Child
  • Child, Preschool
  • Exome Sequencing
  • Exons / genetics
  • Female
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Muscular Atrophy, Spinal / diagnosis*
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / pathology
  • Neuromuscular Diseases / diagnosis*
  • Neuromuscular Diseases / genetics
  • Neuromuscular Diseases / physiopathology
  • Pathology, Molecular*
  • Point Mutation
  • Sequence Deletion
  • Survival of Motor Neuron 1 Protein / genetics
  • Whole Genome Sequencing
  • Young Adult


  • SMN1 protein, human
  • Survival of Motor Neuron 1 Protein