Truncating CLCN1 mutations in myotonia congenita: Variable patterns of inheritance

Authors

  • Randal C. Richardson MD, MMS,

    1. Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Washington, and Seattle Children's Hospital, Seattle, Washington, USA
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  • Jack C. Tarleton PhD,

    1. Fullerton Genetics Laboratory, Mission Hospitals, Asheville, North Carolina, USA
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  • Thomas D. Bird MD,

    1. Geriatric Research Education Clinical Center, VA Puget Sound Health Care System, and Department of Neurology, University of Washington, Seattle, Washington, USA
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  • Sidney M. Gospe Jr. MD, PhD

    Corresponding author
    1. Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Washington, and Seattle Children's Hospital, Seattle, Washington, USA
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  • Dr. Bird has received licensing fees from Athena Diagnostics, Inc. Mission Hospitals' Fullerton Genetics Laboratory has provided in-kind support for analysis and interpretation of DNA sequence data for patients included in the study. Dr. Tarleton is an employee of this nonprofit institution. All remaining authors have nothing to disclose.

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. Muscle Nerve 49:593–600, 2014

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