Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: a study of 680 patients

Research output: Contribution to journalResearch articleContributedpeer-review


  • Angela Abicht - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Marina Dusl - (Author)
  • Constanze Gallenmüller - (Author)
  • Velina Guergueltcheva - (Author)
  • Ulrike Schara - (Author)
  • Adele Della Marina - (Author)
  • Eva Wibbeler - (Author)
  • Sybille Almaras - (Author)
  • Violeta Mihaylova - (Author)
  • Maja von der Hagen - , Department of Paediatrics, Division of Neuropediatrics (Author)
  • Angela Huebner - , Department of Paediatrics (Author)
  • Amina Chaouch - (Author)
  • Juliane S Müller - , Newcastle University (Author)
  • Hanns Lochmüller - (Author)


Congenital myasthenic syndromes (CMSs) are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. Even though CMSs are genetic disorders, they are highly treatable, and the appropriate drug treatment depends on the underlying genetic defect. This highlights the importance of genetic testing in CMS. In recent years, the molecular basis of CMS has constantly broadened and disease-associated mutations have been identified in 14 genes encoding proteins of the neuromuscular junction. In the dawn of novel sequencing strategies, we report on our 14-year experience in traditional Sanger-based mutation screening of a large cohort of 680 independent patients with suspected CMS. In total, we identified disease-causing mutations in 299 patients (44%) of patients in various known CMS genes, confirming the high degree of genetic heterogeneity associated with the disease. Apart from four known founder mutations, and a few additional recurrent mutations, the majority of variants are private, found in single families. The impact of previously reported genotype-phenotype correlations on efficiency of genetic testing was analyzed in our population. Taking our experiment into account, we present our algorithm for genetic testing in CMS.


Original languageEnglish
Pages (from-to)1474-1484
Number of pages11
JournalHuman Mutation
Issue number10
Publication statusPublished - Oct 2012

External IDs

PubMed 22678886
researchoutputwizard legacy.publication#48092
Scopus 84866272011



  • Cohort Studies, Female, Genetic Association Studies, Genetic Heterogeneity, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Myasthenic Syndromes, Congenital/diagnosis, Receptors, Cholinergic/genetics