Abstract
Myotonia congenita (MC) is a Mendelian inherited genetic disease caused by the mutations in the CLCN1 gene, encoding the main skeletal muscle ion chloride channel (ClC-1). The clinical diagnosis of MC should be suspected in patients presenting myotonia, warm-up phenomenon, a characteristic electromyographic pattern, and/or family history. Here, we describe the largest cohort of MC Spanish patients including their relatives (up to 102 individuals). Genetic testing was performed by CLCN1 sequencing and multiplex ligation-dependent probe amplification (MLPA). Analysis of selected exons of the SCN4A gene, causing paramyotonia congenita, was also performed. Mutation spectrum and analysis of a likely founder effect of c.180+3A>T was achieved by haplotype analysis and association tests. Twenty-eight different pathogenic variants were found in the CLCN1 gene, of which 21 were known mutations and seven not described. Gross deletions/duplications were not detected. Four probands had a pathogenic variant in SCN4A. Two main haplotypes were detected in c.180+3A>T carriers and no statistically significant differences were detected between case and control groups regarding the type of haplotype and its frequencies. A diagnostic yield of 51% was achieved; of which 88% had pathogenic variants in CLCN1 and 12% in SCN4A. The existence of a c.180+3A>T founder effect remains unsolved.
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Acknowledgements
We thank Ruben de Sancho and Amparo García Cardenal for their technical contribution in carrying out the experiments and Rocio Mena and Maria Victoria Gomez for capillary sequencing work. We also thank Will Brooks for improving the English language. This work was supported by a fellowship from the ‘Fundación J.L. Castaño’ in 2013 to C. Palma. CLCN1 gene homepage - Shared database [WWW Document], n.d. URL https://databases.lovd.nl/shared/genes/CLCN1(accessed4.18.18).
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Palma Milla, C., Prior De Castro, C., Gómez-González, C. et al. Myotonia congenita: mutation spectrum of CLCN1 in Spanish patients. J Genet 98, 71 (2019). https://doi.org/10.1007/s12041-019-1115-0
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DOI: https://doi.org/10.1007/s12041-019-1115-0