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

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

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Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute of Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany.
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Dokuz Eylül University, Department of Pediatric Neurology, Izmir, Turkey.
Mashhad University of Medical Sciences, Department of Neurology, Mashhad, Iran.
Next Generation Genetic Polyclinic, Mashhad, Iran.
Razavi Cancer Research Center, Razavi Hospital, Imam Reza International University, Mashhad, Iran.
University Hospital Cologne, Department of Neurology, Cologne, Germany.
Hacettepe University, Department of Pediatric Neurology, Ankara, Turkey.
Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
DKD HELIOS Kliniken, Department of Neurology, Wiesbaden, Germany.
Genetics and Molecular Cell Sciences Research Centre, St George's University of London, London, UK.
deCODE Genetics/Amgen, Inc, Reykjavik, Iceland.


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.


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


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