Kang Peter B, Jorand-Fletcher Magali, Zhang Wanfang, McDermott Suzanne W, Berry Reba, Chambers Chelsea, Wong Kristen N, Mohamed Yara, Thomas Shiny, Venkatesh Y Swamy, Westfield Christina, Whitehead Nedra, Johnson Nicholas E
From 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.
Neurol Genet. 2023 Nov 17;9(6):e200113. doi: 10.1212/NXG.0000000000200113. eCollection 2023 Dec.
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.
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 STAR). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation.
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 () and autosomal genes reported to have skewed gender ratios (, , and ). The most common associated genes were , , , and . 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.
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.
报告美国6个地理区域中埃默里 - 德赖富斯肌营养不良症（Emery-Dreifuss muscular dystrophy，EDMD）、肢带型肌营养不良症（limb-girdle muscular dystrophy，LGMD）、先天性肌营养不良症（congenital muscular dystrophy，CMD）和远端肌营养不良症（distal muscular dystrophy，DD）的遗传病因。
这是一项基于人群的横断面研究，我们研究了2008年1月1日至2016年12月31日期间在美国肌肉营养不良监测、追踪和研究网络（MD STAR）覆盖的6个区域中被诊断为EDMD、LGMD、CMD和DD并接受治疗的个体中与肌营养不良相关的基因和变异。对原始基因检测报告中意义未明的变异（variants of unknown significance，VUSs）重新分析以确定解读的变化。
在243例确诊或可能患有肌营养不良症的个体中，LGMD是最常见的诊断类型（138例），其次是CMD（62例）、DD（22例）和EDMD（21例）。男性个体比例高于女性个体，在排除X连锁基因以及据报道具有性别比例偏倚的常染色体基因（、和）后，这种情况仍然存在。最常见的相关基因是、、和。重新分析使144个VUSs中的60个有了更明确的变异解读，所有144个VUSs的原始临床基因检测平均间隔时间为8.11年，60个重新分类的变异为8.62年。发现10名个体在已知主要为隐性的基因中存在单等位基因致病性变异。
本研究的独特之处在于对美国特定地理区域内的4种类型肌营养不良症进行了检查。显著比例的VUSs得到解决证明了定期重新检查这些变异的价值。这种重新检查将在启动重复检测或更具侵入性的诊断程序（如肌肉活检）之前解决一些基因诊断的模糊性。我们队列中隐性基因存在单等位基因致病性变异表明，一些患有肌营养不良症的个体仍然面临不完全的基因诊断；基因知识和诊断方法的进一步完善将为这些个体优化诊断信息。
