Hiraide Takuya, Ogata Tsutomu, Watanabe Seiji, Nakashima Mitsuko, Fukuda Tokiko, Saitsu Hirotomo
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Brain Dev. 2019 May;41(5):474-479. doi: 10.1016/j.braindev.2019.01.005. Epub 2019 Feb 2.
Whole-exome sequencing (WES) can comprehensively detect both pathogenic single nucleotide variants and copy number variants, enabling identification of a coexistence of two or more genetic etiologies. Here we report a family consisting of individuals with Becker muscular dystrophy and rippling muscle disease. The proband, a 12-year-old boy, was diagnosed with Becker muscular dystrophy with exon 45-55 DMD deletions at age 4. He had myalgia and muscle stiffness. Interestingly, percussion-induced muscle mounding (PIMM), which is a characteristic of rippling muscle disease, was also observed. The father also showed muscle stiffness, myalgia, fatigability, muscle rippling and PIMM. WES revealed a missense CAV3 mutation (NM_033337.2:c.80G>A) in the proband, the father, the oldest sister and the grandmother, who had an elevated serum creatine kinase (CK) level. The c.80G>A mutation was considered pathogenic according to ACMG guidelines. The second older sister, the mother and the paternal grandfather did not have the CAV3 mutation and had normal CK. Using two programs for copy number analysis with WES data, we successfully identified the DMD deletion in the proband, the older sister and the mother. We revealed the coexistence of the CAV3 mutation and the DMD deletion in a family with complex muscular diseases and confirmed the usefulness of WES for elucidating such etiology.
全外显子组测序（WES）能够全面检测致病性单核苷酸变异和拷贝数变异，从而识别两种或更多种遗传病因的共存情况。在此，我们报告一个由患有贝克型肌营养不良症和波纹状肌病的个体组成的家系。先证者是一名12岁男孩，4岁时被诊断为伴有外显子45 - 55 DMD缺失的贝克型肌营养不良症。他有肌痛和肌肉僵硬症状。有趣的是，还观察到了敲击诱发的肌肉隆起（PIMM），这是波纹状肌病的一个特征。父亲也表现出肌肉僵硬、肌痛、易疲劳、肌肉波纹和PIMM。WES显示先证者、父亲、大姐和祖母存在错义CAV3突变（NM_033337.2:c.80G>A），他们的血清肌酸激酶（CK）水平升高。根据美国医学遗传学与基因组学学会（ACMG）指南，c.80G>A突变被认为是致病性的。二姐、母亲和祖父没有CAV3突变，且CK水平正常。使用两个程序对WES数据进行拷贝数分析，我们成功在先证者、大姐和母亲中鉴定出DMD缺失。我们揭示了一个患有复杂肌肉疾病的家系中CAV3突变和DMD缺失的共存情况，并证实了WES在阐明此类病因方面的实用性。
