Association of Three Different Mutations in the CLCN1 Gene Modulating the Phenotype in a Consanguineous Family with Myotonia Congenita

Abstract

Myotonia congenita is a genetic disease caused by mutations in the CLCN1 gene, which encodes for the major chloride skeletal channel ClC-1, involved in the normal repolarization of muscle action potentials and consequent relaxation of the muscle after contraction. Two allelic forms are recognized, depending on the phenotype and the inheritance pattern: the autosomal dominant Thomsen disease with milder symptoms and the autosomal recessive Becker disorder with a severe phenotype. Before the recent advances of molecular testing, the diagnosis and genetic counseling of families was a challenge due to the large number of mutations in the CLCN1 gene, found both in homozygous or in heterozygous state. Here, we studied a consanguineous family in which three members presented a variable phenotype of myotonia, associated to a combination of three different mutations in the CLCN1 gene. A pathogenic splicing site mutation which causes the skipping of exon 17 was present in homozygosis in one very severely affected son. This mutation was present in compound heterozygosis in the consanguineous parents, but interestingly it was associated to a different second variant in the other allele: c.1453 A > G in the mother and c.1842 G > C in the father. Both displayed variable, but less severe phenotypes than their homozygous son. These results highlight the importance of analyzing the combination of different variants in the same gene in particular in families with patients displaying different phenotypes. This approach may improve the diagnosis, prognosis, and genetic counseling of the involved families.

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Acknowledgments

We would like to thank Fundação de Amparo à Pesquisa do Estado de São Paulo—Centro de Pesquisa, Inovação e Difusão (FAPESP-CEPID), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Instituto Nacional de Ciência e Tecnologia (INCT), FINEP, for the financial support. We would also like to thank the technical support of the following researchers: Adriano S. Senkevics, Dinorah Zilbersztajn-Gotlieb, Lydia U. Yamamoto, Viviane P. Muniz, and Leticia Nogueira. We are also very grateful to Dr. Paula Onofre-Oliveira for the English correction and improvement.

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo—Centro de Pesquisa, Inovação e Difusão (FAPESP-CEPID), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Instituto Nacional de Ciência e Tecnologia (INCT), FINEP.

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Lucas Santos Souza conceived, designed, and performed the analysis and elaborated, wrote, and reviewed the manuscript. Priscila Calyjur performed the analysis. Antonio Fernando Ribeiro Jr performed the muscle protein analysis. Juliana Gurgel-Giannetti performed the medical and/or physical evaluation of the patients, and contributed with the manuscript revision. Rita Cassia Mingroni Pavanello performed the medical and/or physical evaluation of the patients. Mayana Zatz performed the genetic counseling and contributed with the manuscript revision. Mariz Vainzof conceived, designed, and performed the analysis and elaborated, wrote, and reviewed the manuscript.

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Correspondence to Mariz Vainzof.

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This work is in accordance and was approved by the ethics committee of the Biosciences Institute of the University of Sao Paulo, and the DNA samples are deposited in the biobank repository of the Human Genome and Stem Cells Research Center of IB-USP.

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Souza, L.S., Calyjur, P., Ribeiro, A.F. et al. Association of Three Different Mutations in the CLCN1 Gene Modulating the Phenotype in a Consanguineous Family with Myotonia Congenita. J Mol Neurosci (2021). https://doi.org/10.1007/s12031-020-01785-4

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Keywords

  • Congenital myotonia
  • Phenotypic variability
  • Genotypic variability