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Published on: January 31, 2013
Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research
Peter B Kang1, Magali Jorand-Fletcher1, Wanfang Zhang1
1From the Paul & Sheila Wellstone Muscular Dystrophy Center (P.B.K.), Department of Neurology, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis; Department of Pediatrics (M.J.-F., Y.M.), University of Florida College of Medicine, Gainesville; Department of Epidemiology and Biostatistics (W.Z.), University of South Carolina, Columbia; Department of Environmental, Occupational, and Geospatial Health Sciences (S.W.M.), Graduate School of Public Health and Health Policy, City University of New York; Division of Population Health Surveillance (R.B., C.W.), Bureau of Maternal and Child Health, South Carolina Department of Health and Environmental Control, Columbia; Department of Human and Molecular Genetics (C.C.), Virginia Commonwealth University, Richmond; Department of Pediatrics (K.N.W.), University of Utah, Salt Lake City; New York State Department of Health (S.T.), Albany; Department of Neurology (Y.S.V.), University of South Carolina, Columbia; RTI International (N.W.), Research Triangle Park, NC; and Department of Neurology (N.E.J.), Virginia Commonwealth University, Richmond.
Background And Objectives:
To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States.
Methods:
This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy in individuals who were diagnosed with and received care for EDMD, LGMD, CMD, and DD from January 1, 2008, through December 31, 2016, in the 6 areas of the United States covered by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation.
Results:
Among 243 individuals with definite or probable muscular dystrophy, LGMD was the most common diagnosis (138 cases), followed by CMD (62 cases), DD (22 cases), and EDMD (21 cases). There was a higher proportion of male individuals compared with female individuals, which persisted after excluding X-linked genes (EMD) and autosomal genes reported to have skewed gender ratios (ANO5, CAV3, and LMNA). The most common associated genes were FKRP, CAPN3, ANO5, and DYSF. Reanalysis yielded more definitive variant interpretations for 60 of 144 VUSs, with a mean interval between the original clinical genetic test of 8.11 years for all 144 VUSs and 8.62 years for the 60 reclassified variants. Ten individuals were found to have monoallelic pathogenic variants in genes known to be primarily recessive.
Discussion:
This study is distinct for being an examination of 4 types of muscular dystrophies in selected geographic areas of the United States. The striking proportion of resolved VUSs demonstrates the value of periodic re-examinations of these variants. Such re-examinations will resolve some genetic diagnostic ambiguities before initiating repeat testing or more invasive diagnostic procedures such as muscle biopsy. The presence of monoallelic pathogenic variants in recessive genes in our cohort indicates that some individuals with muscular dystrophy continue to face incomplete genetic diagnoses; further refinements in genetic knowledge and diagnostic approaches will optimize diagnostic information for these individuals.
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