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Targeted sequencing with expanded gene profile enables high diagnostic yield in non‐5q‐spinal muscular atrophies
Author(s) -
Karakaya Mert,
Storbeck Markus,
Strathmann Eike A.,
Delle Vedove Andrea,
Hölker Irmgard,
Altmueller Janine,
Naghiyeva Leyla,
SchmitzSteinkrüger Lea,
Vezyroglou Katharina,
Motameny Susanne,
Alawbathani Salem,
Thiele Holger,
Polat Ayse Ipek,
Okur Derya,
Boostani Reza,
Karimiani Ehsan Ghayoor,
Wunderlich Gilbert,
Ardicli Didem,
Topaloglu Haluk,
Kirschner Janbernd,
Schrank Bertold,
Maroofian Reza,
Magnusson Olafur,
Yis Uluc,
Nürnberg Peter,
Heller Raoul,
Wirth Brunhilde
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23560
Subject(s) - smn1 , sma* , spinal muscular atrophy , biology , genetics , exome sequencing , gene , neuromuscular disease , hypotonia , bioinformatics , disease , mutation , pathology , medicine , mathematics , combinatorics
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.