Karakaya, Mert ORCID: 0000-0001-5395-8894, Storbeck, Markus, Strathmann, Eike A., Delle Vedove, Andrea, Hoelker, Irmgard, Altmueller, Janine, Naghiyeva, Leyla, Schmitz-Steinkrueger, 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 ORCID: 0000-0003-1618-7386, Schrank, Bertold, Maroofian, Reza, Magnusson, Olafur, Yis, Uluc, Nuernberg, Peter, Heller, Raoul and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2018). Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies. Hum. Mutat., 39 (9). S. 1284 - 1299. HOBOKEN: WILEY. ISSN 1098-1004

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Karakaya, MertUNSPECIFIEDorcid.org/0000-0001-5395-8894UNSPECIFIED
Storbeck, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strathmann, Eike A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delle Vedove, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelker, IrmgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naghiyeva, LeylaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitz-Steinkrueger, LeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vezyroglou, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alawbathani, SalemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polat, Ayse IpekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okur, DeryaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boostani, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karimiani, Ehsan GhayoorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, GilbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ardicli, DidemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Topaloglu, HalukUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirschner, JanberndUNSPECIFIEDorcid.org/0000-0003-1618-7386UNSPECIFIED
Schrank, BertoldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maroofian, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Magnusson, OlafurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yis, UlucUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heller, RaoulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
URN: urn:nbn:de:hbz:38-173645
DOI: 10.1002/humu.23560
Journal or Publication Title: Hum. Mutat.
Volume: 39
Number: 9
Page Range: S. 1284 - 1299
Date: 2018
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ARTHROGRYPOSIS MULTIPLEX CONGENITA; HEREDITARY MOTOR NEUROPATHY; MARIE-TOOTH DISEASE; MYASTHENIC SYNDROME; NEUROMUSCULAR DISEASES; MUTATION SPECTRUM; RARE DISEASES; PHENOTYPE; BICD2; VARIANTSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17364

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