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

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Item Type:	Article
Title:	Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies
Creators Name:	Karakaya, M., Storbeck, M., Strathmann, E.A., Delle Vedove, A., Hölker, I., Altmueller, J., Naghiyeva, L., Schmitz-Steinkrüger, L., Vezyroglou, K., Motameny, S., Alawbathani, S., Thiele, H., Polat, A.I., Okur, D., Boostani, R., Karimiani, E.G., Wunderlich, G., Ardicli, D., Topaloglu, H., Kirschner, J., Schrank, B., Maroofian, R., Magnusson, O., Yis, U., Nürnberg, P., Heller, R. and Wirth, B.
Abstract:	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
Source:	Human Mutation
ISSN:	1059-7794
Publisher:	Wiley
Volume:	39
Number:	9
Page Range:	1284-1298
Date:	September 2018
Official Publication:	https://doi.org/10.1002/humu.23560
PubMed:	View item in PubMed

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