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Muscle Nerve. 2014 Apr;49(4):593-600. doi: 10.1002/mus.23976. Epub 2013 Sep 20.

Truncating CLCN1 mutations in myotonia congenita: variable patterns of inheritance.

Author information

1
Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Washington, and Seattle Children's Hospital, 4800 Sand Point Way NE, Neurology, MB.7.420, Seattle, Washington, USA, 98105.

Abstract

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.

KEYWORDS:

CLC-1; CLCN1; allelic variability; myotonia; myotonia congenita

PMID:
23893571
DOI:
10.1002/mus.23976
[Indexed for MEDLINE]

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