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Neurology Genetics
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December 2015; 1 (4) ArticleOpen Access

Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing

Rumiko Izumi, Tetsuya Niihori, Toshiaki Takahashi, Naoki Suzuki, Maki Tateyama, Chigusa Watanabe, Kazuma Sugie, Hirotaka Nakanishi, Gen Sobue, Masaaki Kato, Hitoshi Warita, Yoko Aoki, Masashi Aoki
First published December 10, 2015, DOI: https://doi.org/10.1212/NXG.0000000000000036
Rumiko Izumi
From the 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.
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Tetsuya Niihori
From the 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.
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Toshiaki Takahashi
From the 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.
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Naoki Suzuki
From the 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.
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Maki Tateyama
From the 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.
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Chigusa Watanabe
From the 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.
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Kazuma Sugie
From the 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.
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Hirotaka Nakanishi
From the 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.
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Gen Sobue
From the 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.
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Masaaki Kato
From the 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.
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Hitoshi Warita
From the 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.
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Yoko Aoki
From the 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.
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Masashi Aoki
From the 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.
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Citation
Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing
Rumiko Izumi, Tetsuya Niihori, Toshiaki Takahashi, Naoki Suzuki, Maki Tateyama, Chigusa Watanabe, Kazuma Sugie, Hirotaka Nakanishi, Gen Sobue, Masaaki Kato, Hitoshi Warita, Yoko Aoki, Masashi Aoki
Neurol Genet Dec 2015, 1 (4) e36; DOI: 10.1212/NXG.0000000000000036

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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.

GLOSSARY

CK=
creatine kinase;
DM=
distal myopathy;
HGMD=
Human Gene Mutation Database;
LGMD=
limb-girdle muscular dystrophy;
MLPA=
multiplex ligation-dependent probe amplification;
MMD=
Miyoshi muscular dystrophy;
XHMM=
eXome-Hidden Markov Model

Footnotes

  • Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors.

  • Supplemental data at Neurology.org/ng

  • See editorial

  • See related article

  • Received August 24, 2015.
  • Accepted in final form October 26, 2015.
  • © 2015 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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