Association of Three Different Mutations in the CLCN1 Gene Modulating the Phenotype in a Consanguineous Family with Myotonia Congenita.
J Mol Neurosci
; 71(11): 2275-2280, 2021 Nov.
Article
en En
| MEDLINE
| ID: mdl-33464536
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenotipo
/
Canales de Cloruro
/
Mutación
/
Miotonía Congénita
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Mol Neurosci
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Brasil
Pais de publicación:
Estados Unidos