Truncating CLCN1 mutations in myotonia congenita: Variable patterns of inheritance

Introduction: Myotonia congenita due to protein truncating CLCN1 mutations is associated with variable patterns of inheritance. Methods: Three family kindreds are described, all of whom possess protein truncating mutations (Y33X, fs503X, R894X). One lineage also has coexistent R894X, A313T, and A320V mutations. Results: The Y33X mutation kinship has autosomal recessive inheritance and a severe phenotype when homozygous. The fs503X family has autosomal dominant inheritance and a moderate-to-severe phenotype. The A313T mutation kindred also has autosomal dominant inheritance but expresses a mild phenotype, except for the more severely affected compound heterozygotes. Conclusions: Early truncating mutations precluding dimerization are expected to be autosomal recessive and express a severe phenotype, while later mutations may be variable. The pedigrees presented here demonstrate that intrafamilial phenotypic variability may result from a dosage effect of an additional mutation, not necessarily variable expressivity. Mutations that have unexpected patterns of inheritance may represent allelic variability. Muscle Nerve 49:593–600, 2014