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

Abstract

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.

• Authors: Angela Abicht, Marina Dusl, Constanze Gallenmüller, Velina Guergueltcheva, Ulrike Schara, Adele Della Marina, Eva Wibbeler, Sybille Almaras, Violeta Mihaylova, Maja von der Hagen, Angela Huebner, Amina Chaouch, Juliane S Müller, Hanns Lochmüller
• Journal: Human mutation (Hum Mutat) Vol. 33 Issue 10 Pg. 1474-84 (Oct 2012) ISSN: 1098-1004 [Electronic] United States
• PMID: 22678886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Wiley Periodicals, Inc.

Chemical References

• Receptors, Cholinergic

Topics

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