RT Journal Article
SR Electronic
T1 Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e36
DO 10.1212/NXG.0000000000000036
VO 1
IS 4
A1 Izumi, Rumiko
A1 Niihori, Tetsuya
A1 Takahashi, Toshiaki
A1 Suzuki, Naoki
A1 Tateyama, Maki
A1 Watanabe, Chigusa
A1 Sugie, Kazuma
A1 Nakanishi, Hirotaka
A1 Sobue, Gen
A1 Kato, Masaaki
A1 Warita, Hitoshi
A1 Aoki, Yoko
A1 Aoki, Masashi
YR 2015
UL http://ng.neurology.org/content/1/4/e36.abstract
AB 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.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