Journal of Neurology

, Volume 263, Issue 4, pp 743–750 | Cite as

Utility of a next-generation sequencing-based gene panel investigation in German patients with genetically unclassified limb-girdle muscular dystrophy

  • Marius Kuhn
  • Dieter Gläser
  • Pushpa Raj Joshi
  • Stephan Zierz
  • Stephan Wenninger
  • Benedikt Schoser
  • Marcus Deschauer
Original Communication


Limb-girdle muscular dystrophies (LGMDs) are genetically heterogeneous and the diagnostic work-up including conventional genetic testing using Sanger sequencing remains complex and often unsatisfactory. We performed targeted sequencing of 23 LGMD-related genes and 15 genes in which alterations result in a similar phenotype in 58 patients with genetically unclassified LGMDs. A genetic diagnosis was possible in 19 of 58 patients (33 %). LGMD2A was the most common form, followed by LGMD2L and LGMD2I. In two patients, pathogenic mutations were identified in genes that are not classified as LGMD genes (glycogen branching enzyme and valosin-containing protein). Thus, a focused next-generation sequencing-based gene panel is a rather satisfactory tool for the diagnosis in unclassified LGMDs.


Limb-girdle muscular dystrophies Gene panel Targeted next-generation sequencing 

Supplementary material

415_2016_8036_MOESM1_ESM.docx (35 kb)
Supplementary material 1 (DOCX 35 kb)


  1. 1.
    Nigro V, Savarese M (2014) Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol 33:1–12PubMedPubMedCentralGoogle Scholar
  2. 2.
    Murphy AP, Straub V (2015) The classification, natural history and treatment of the limb girdle muscular dystrophies. J Neuromuscul Dis 2:7–19CrossRefGoogle Scholar
  3. 3.
    Kaplan JC, Hamroun D (2012) The 2013 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscul Disord 22:1108–1135CrossRefPubMedGoogle Scholar
  4. 4.
    Ghosh PS, Zhou L (2012) The diagnostic utility of a commercial limb-girdle muscular dystrophy gene test panel. J Clin Neuromuscul Dis 14:86–87CrossRefPubMedGoogle Scholar
  5. 5.
    Seong MW, Cho A, Park HW, Seo SH, Lim BC, Seol D, Cho SI, Park SS, Chae JH (2015) Clinical applications of next-generation sequencing-based gene panel in patients with muscular dystrophy: Korean experience. Clin Genet (Epub ahead of print)Google Scholar
  6. 6.
    Dai Y, Wei X, Zhao Y, Ren H, Lan Z, Yang Y, Chen L, Cui L (2015) A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing. Neuromuscul Disord 25:617–624CrossRefPubMedGoogle Scholar
  7. 7.
    Bartoli M, Desvignes JP, Nicolas L, Martin K (2014) Exome sequencing as a second-tier diagnostic approach for clinically suspected dysferlinopathy patients. Muscle Nerve 50:1007–1010CrossRefPubMedGoogle Scholar
  8. 8.
    Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, Needham M, Liang C, Waddell LB, Nicholson G, O’Grady G, Kaur S, Ong R, Davis M, Sue CM, Laing NG, North KN, MacArthur DG, Clarke NF (2015) Use of whole-exome sequencing for diagnosis of limb-girdle muscular dystrophy: outcomes and lessons learned. JAMA Neurol 72:1424–1432CrossRefPubMedGoogle Scholar
  9. 9.
    Fanin M, Angelini C (2015) Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: the yield and the pitfalls. Muscle Nerve 52:163–173CrossRefPubMedGoogle Scholar
  10. 10.
    Savarese M, Di Fruscio G, Tasca G, Ruggiero L, Janssens S, De Bleecker J, Delpech M, Musumeci O, Toscano A, Angelini C, Sacconi S, Santoro L, Ricci E, Claes K, Politano L, Nigro V (2015) Next generation sequencing on patients with LGMD and nonspecific myopathies: findings associated with ANO5 mutations. Neuromuscul Disord 25:533–541CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V (2009) Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain 132:3175–3186CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bruno C, van Diggelen OP, Cassandrini D, Gimpelev M, Giuffrè B, Donati MA, Introvini P, Alegria A, Assereto S, Morandi L, Mora M, Tonoli E, Mascelli S, Traverso M, Pasquini E, Bado M, Vilarinho L, van Noort G, Mosca F, DiMauro S, Zara F, Minetti C (2004) Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 63:1053–1058CrossRefPubMedGoogle Scholar
  13. 13.
    Fernandez C, Halbert C, De Paula AM, Lacroze V, Froissart R, Figarella-Branger D, Chabrol B, Pellissier JF (2010) Non-lethal neonatal neuromuscular variant of glycogenosis type IV with novel GBE1 mutations. Muscle Nerve 41:269–271PubMedGoogle Scholar
  14. 14.
    Krause S, Göhringer T, Walter MC, Schoser BG, Reilich P, Linn J, Pöpperl GE, Frölich L, Hentschel F, Lochmüller H, Danek A (2007) Brain imaging and neuropsychology in late-onset dementia due to a novel mutation (R93C) of valosin-containing protein. Clin Neuropathol 26:232–240CrossRefPubMedGoogle Scholar
  15. 15.
    Momma K, Noguchi S, Malicdan MCV, Hayashi YK, Minami N, Kamakura K, Nishino I (2012) Rimmed vacuoles in becker muscular dystrophy have similar features with inclusion myopathies. PLoS One 7:e52002CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Di Fruscio G, Garofalo A, Mutarelli M, Savarese M, Nigro V (2016) Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic? Eur J Hum Genet 24:73–77CrossRefPubMedGoogle Scholar
  17. 17.
    van Dijk EL, Auger H, Jaszczyszyn Y, Thermes C (2014) Ten years of next-generation sequencing technology. Trends Genet 30:418–426CrossRefPubMedGoogle Scholar
  18. 18.
    Kaplan JC, Hamroun D (2015) The 2016 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscul Disord 25:991–1020CrossRefGoogle Scholar
  19. 19.
    Savarese M, Di Fruscio G, Mutarelli M, Torella A, Magri F, Santorelli F, Comi G, Bruno C, Nigro V (2014) MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples. Acta Neuropathol Commun 2:100CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vasli N, Böhm J, Gras SL, Muller J, Pizot C, Jost B, Echaniz-Laguna A, Laugel V, Tranchant C, Bernard R, Plewniak F, Vicaire S, Levy N, Chelly J, Mandel J-L, Biancalana V, Laporte J (2012) Next generation sequencing for molecular diagnosis of neuromuscular diseases. Acta Neuropathol 124:273–283CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ankala A, da Silva C, Gualandi F, Ferlini A, Bean LJ, Collins C, Tanner AK, Hegde MR (2015) A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield. Ann Neurol 77:206–214CrossRefPubMedGoogle Scholar
  22. 22.
    Biesecker LG, Green RC (2014) Diagnostic clinical genome and exome sequencing. N Engl J Med 370:2418–2425CrossRefPubMedGoogle Scholar
  23. 23.
    Valencia CA, Ankala A, Rhodenizer D, Bhide S, Littlejohn MR, Keong LM, Rutkowski A, Sparks S, Bonnemann C, Hegde M (2013) Comprehensive mutation analysis for congenital muscular dystrophy: a clinical PCR-based enrichment and next-generation sequencing panel. PLoS One 8:e53083CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gorokhova S, Biancalana V, Lévy N, Laporte J, Bartoli M, Krahn M (2015) Clinical massively parallel sequencing for the diagnosis of myopathies. Rev Neurol (Paris) 171:558–571CrossRefGoogle Scholar
  25. 25.
    Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 369:1502–1511CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Marius Kuhn
    • 1
    • 2
  • Dieter Gläser
    • 1
  • Pushpa Raj Joshi
    • 3
  • Stephan Zierz
    • 3
  • Stephan Wenninger
    • 4
  • Benedikt Schoser
    • 4
  • Marcus Deschauer
    • 3
    • 5
  1. 1.GenetikumNeu-UlmGermany
  2. 2.Division of NeurophysiologyUniversität UlmUlmGermany
  3. 3.Klinik und Poliklinik für NeurologieUniversität Halle-WittenbergHalleGermany
  4. 4.Friedrich-Baur-Institut, Neurologische KlinikLudwig-Maximilians-Universität MünchenMunichGermany
  5. 5.Klinik und Poliklinik für Neurologie, Technische Universität München, Klinikum rechts der IsarMunichGermany

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