Neuropediatrics 2016; 47 - PS01-04
DOI: 10.1055/s-0036-1583600

Congenital Myasthenic Syndromes: Efficiency and Pitfalls of Phenotype-Based Gene Panel Testing

L. Feder 1, A. Nissen 1, S. Bulst 1, M. Dusl 2, J. Senderek 2, M. C. Walter 2, U. Schara 3, Marina A. Della 3, Heike Kölbel 3, H. Lochmüller 4, A. Benet-Pagès 1, A. Abicht 1, 2
  • 1Medizinisch Genetisches Zentrum, MGZ, Munich, Germany
  • 2Friedrich-Baur-Institute, Dept. of Neurology, Ludwig-Maximilian’s University of Munich, Germany
  • 3Department of Paediatric Neurology, University of Duisburg-Essen, Germany
  • 4Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

Background/Purpose: Congenital myasthenic syndromes (CMS) are characterized by a neuromuscular transmission defect and display as clinically and genetically heterogeneous disorders. As genetic disorders, CMS are exceptional in that they are highly treatable. However, the appropriate drug treatment depends on the underlying genetic defect. This implicates the special importance of genetic testing. The constantly growing number of known disease-associated genes has enlarged the molecular basis of CMS and is limiting single gene testing.

Methods: We report on a cohort of 50 CMS patients tested by diagnostic gene panels. Diagnostic efficiency of a focused and a broader phenotype-based selection of CMS genes are compared respecting diagnostic yield and precision. Patients were consecutively tested for 14 genes, focused on the phenotype of CMS, a congenital myopathy panel (35 genes), and for a comprehensive neuromuscular panel (370 genes).

Results: Analysis of the CMS panel revealed a diagnostic yield of ~35%. We failed to significantly increase the diagnostic yield by a second-tier (congenital myopathies) and third-tier (neuromuscular disorders) analysis of larger gene panels. As an unsolicited side effect there is a significant increase in the number of variants with unknown significance if large panels far from the core phenotype are tested.

Conclusion: We conclude that even in the era of next-generation sequencing, detailed clinical data as well as the inclusion of parental genetic data are prerequisite for a precise molecular diagnosis.