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Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing
Rumiko Izumi1, Tetsuya Niihori1, Toshiaki Takahashi1
1Departments 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.
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.
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