Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations

PURPOSE: This study was designed to investigate the characteristics of Korean patients with calpainopathy. MATERIALS AND METHODS: Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed. RESULTS: Nine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology. CONCLUSION: We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.

Clinical and molecular genetic study of limb-girdle muscular dystrophy type 2A in a Chinese family / 中华实用儿科临床杂志

Objective To analyze the clinical,muscle pathological features and molecular mutations in the 2 Chinese Han siblings with limb-girdle muscular dystrophy(LGMD) and conclude the phenotype/genotype correlations.Methods Clinical and muscle pathological data were collected.Genomic DNA of the two siblings and their parents were extracted using standard procedures from the peripheral leukocytes.A custom of targeted gene panel including 61 neuromuscular genes were designed by using the Agilent Sureselect Target Enrichment Kit.Targeted next generation sequencing(NGS) was performed in the proband,and CAPN3 gene mutation was verified with Sanger sequencing in the two siblings and their parents.The dbSNP138 and http://www.dmd.nl were searched to determine the disease-causing mutations.Results The proband slowly showed muscle weakness profoundly with pelvic muscles,developed difficulty in squatting and standing and climbing stairs.She had a tight Achilles tendon,high CK level (1 908-9 241 IU/L),without winging scapula and hypertrophy calf.The affected brother was only diagnosed hyper CKemia.By using the targeted NGS,the two siblings possessed the same two compound heterozygous mutations(c.717delT and c.2243G ＞ A) in CAPN3 gene.The two mutations both were verified by Sanger sequencing and had been reported before.Conclusions LGMD is clinically and genetically heterogeneous,and targeted NGS is powerful in defining the causal mutation of LGMD and helpful in investigating the exact genotype/phenotype analysis.