To investigate the genetic causes of suspected dysferlinopathy and to reveal the genetic profile for myopathies with dysferlin deficiency.
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.
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).
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.
Served on the scientific advisory boards for Kanae Science Foundation for the Promotion of Medical Science (2009-2010); Naito Science Foundation (2009-2010); Takeda Foundation (2012-present)
(1) Brain, Advisory Board, 2004-present, (2) Degenerative Neurological and Neuromuscular Disease, Editorial Board, 2010-present (3) Editorial Board, Journal of Neurology, 2011-present (4) Editorial Board, Amyotrophic Lateral Sclerosis, 2008-present
Funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan (#21229011, #17025020, #09042025) (2009-present); the Ministry of Welfare, Health and Labor of Japan(2008-present); the Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (2008-present).
(1)the Japanese Ministry of Health Labor and Welfare, Japan, Principal Investigator, 2014 (2)Japan Society for the Promotion of Science (JSPS), Japan, Principal Investigator, 2015 (3)Japan Agency for Medical Research and development (AMED),Japan, Principal Investigator, Investigator, 2015
Masashi Aoki has received research grants, Research on Nervous and Mental disorders, Research on Measures for Intractable Diseases, Research on Psychiatric and Neurological Diseases and Mental Health from the Japanese Ministry of Health Labor and Welfare, Grants-in-Aids for Scientific Research, an Intramural Research Grant for Neurological Psychiatric Disorders from NCNP and Grants-in-Aids for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
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.
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