title: Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing.
abstract: OBJECTIVE
  To investigate the genetic causes of suspected dysferlinopathy and to reveal the genetic profile for myopathies with dysferlin deficiency.
  
  
  METHODS
  Using next-generation sequencing, we analyzed 42 myopathy-associated genes, including DYSF, in 64 patients who were clinically or pathologically suspected of having dysferlinopathy. Putative pathogenic mutations were confirmed by Sanger sequencing. In addition, copy-number variations in DYSF were investigated using multiplex ligation-dependent probe amplification. We also analyzed the genetic profile for 90 patients with myopathy with dysferlin deficiency, as indicated by muscle specimen immunohistochemistry, including patients from a previous cohort.
  
  
  RESULTS
  We identified putative pathogenic mutations in 38 patients (59% of all investigated patients). Twenty-three patients had DYSF mutations, including 6 novel mutations. The remaining 16 patients, including a single patient who also carried the DYSF mutation, harbored putative pathogenic mutations in other genes. The genetic profile for 90 patients with dysferlin deficiency revealed that 70% had DYSF mutations (n = 63), 10% had CAPN3 mutations (n = 9), 2% had CAV3 mutations (n = 2), 3% had mutations in other genes (in single patients), and 16% did not have any identified mutations (n = 14).
  
  
  CONCLUSIONS
  This study clarified the heterogeneous genetic profile for myopathies with dysferlin deficiency. Our results demonstrate the importance of a comprehensive analysis of related genes in improving the genetic diagnosis of dysferlinopathy as one of the most common subtypes of limb-girdle muscular dystrophy. Unresolved diagnoses should be investigated using whole-genome or whole-exome sequencing.
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Izumi
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tateyama
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Chigusa
authors.initials: C
authors.lastname: Watanabe
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Sugie
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kato
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Warita
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Departments of Neurology (R.I., N.S., M.T., M.K., H.W., M.A.) and Medical Genetics (R.I., T.N., Y.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga, National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; Department of Neurology (C.W.), Hiroshima-Nishi Medical Center, Hiroshima, Japan; Department of Neurology (K.S.), Nara Medical University, Nara, Japan; and Department of Neurology (H.N.) and Research Division for Neurodegeneration and Dementia (G.S.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki