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

Karakaya M. , Storbeck M., Strathmann E. A. , Delle Vedove A., Hoelker I., Altmueller J., ...More

HUMAN MUTATION, vol.39, no.9, pp.1284-1298, 2018 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 39 Issue: 9
  • Publication Date: 2018
  • Doi Number: 10.1002/humu.23560
  • Title of Journal : HUMAN MUTATION
  • Page Numbers: pp.1284-1298


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.