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

Item Type:	Article
Title:	Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies
Creators Name:	Karakaya, M. and Storbeck, M. and Strathmann, E.A. and Delle Vedove, A. and Hölker, I. and Altmueller, J. and Naghiyeva, L. and Schmitz-Steinkrüger, L. and Vezyroglou, K. and Motameny, S. and Alawbathani, S. and Thiele, H. and Polat, A.I. and Okur, D. and Boostani, R. and Karimiani, E.G. and Wunderlich, G. and Ardicli, D. and Topaloglu, H. and Kirschner, J. and Schrank, B. and Maroofian, R. and Magnusson, O. and Yis, U. and Nürnberg, P. and 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

Repository Staff Only: item control page