Truncating CLCN1 mutations in myotonia congenita: Variable patterns of inheritance |
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| Authors: | Randal C Richardson MD MMS Jack C Tarleton PhD Thomas D Bird MD Sidney M Gospe Jr MD PhD |
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| Institution: | 1. Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Washington, and Seattle Children's Hospital, , Seattle, Washington, USA, 98105;2. Fullerton Genetics Laboratory, Mission Hospitals, , Asheville, North Carolina, USA;3. 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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| 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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| Keywords: | allelic variability CLC‐1 CLCN1 myotonia myotonia congenita |
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