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Abstract
Background: Muscular dystrophy (MD) includes multiple types, of which dystrophinopathies caused by dystrophin (DMD) mutations are the most common types in children. An accurate identification of the causative mutation at the genomic level is critical for genetic counseling of the family, and analysis of genotype–phenotype correlations, as well as a reference for the development of gene therapy. Methods: Totally, 70 Chinese families with suspected MD probands were enrolled in the study. The multiplex ligation-dependent probe amplification (MLPA) was first performed to screen large deletions/duplications of DMD exons in the patients, and then, next-generation sequencing (NGS) was carried out to detect small mutations in the MLPA-negative patients. Results: Totally, 62 mutations of DMD were found in 62 probands with DMD/BMD, and two compound heterozygous mutations in LAMA2 were identified in two probands with MDC1A (a type of congenital MD), indicating that the diagnostic yield was 91.4% by MLPA plus NGS for MD diagnosis in this cohort. Out of the mutations, 51 large mutations encompassing 47 (75.8%) deletions and four duplications (6.5%) were identified by MLPA; 11 small mutations including six (9.7%) nonsense, two (3.2%) small deletions, two splice-site mutations (3.2%), and one small insertion (1.6%) were found by NGS. Large mutations were found most frequently in the hotspot region between exons 45 and 55 (70.6%). Out of the 11 patients harboring point mutations in DMD, 8 were novel mutations. Additionally, one novel mutation in LAMA2 was identified. All the novel mutations were analyzed and predicted as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guideline. Finally, 34 DMD, 4 BMD, 24 BMD/DMD, and 2 MDC1A were diagnosed in the cohort. Conclusion: Our data indicated that the MLPA plus NGS can be a comprehensive and effective tool for precision diagnosis and potential treatment of MD and is particularly necessary for the patients at very young age with only two clinical indicators (persistent hyperCKemia and typical myopathy performance on electromyogram) but no definite clinical manifestations.
Highlights
Muscular dystrophies (MD), an inherited group of degenerative skeletal muscle disorders, are characterized by progressive/ congenital weakness and breakdown of skeletal muscles encompassing great clinical and genetic heterogeneity, and even death because of cardiomyopathy and respiratory failure (Mercuri and Muntoni, 2013; Falsaperla et al, 2016; Carter et al, 2018)
Totally, 62 mutations of Duchenne MD (DMD) were found in 62 probands with DMD/Becker MD (BMD), and two compound heterozygous mutations in LAMA2 were identified in two probands with MDC1A, indicating that the diagnostic yield was 91.4% by multiplex ligation-dependent probe amplification (MLPA) plus nextgeneration sequencing (NGS) for MD diagnosis in this cohort
The average CK values for these patients clinically diagnosed with DMD and BMD were 17,528.33 ± 10,234.82 U/L and 6,017.71 ± 2,890.50 U/L, respectively, which indicated a significant difference between both categories (P < 0.01) (Table 1)
Summary
Muscular dystrophies (MD), an inherited group of degenerative skeletal muscle disorders, are characterized by progressive/ congenital weakness and breakdown of skeletal muscles encompassing great clinical and genetic heterogeneity, and even death because of cardiomyopathy and respiratory failure (Mercuri and Muntoni, 2013; Falsaperla et al, 2016; Carter et al, 2018). DMD/BMD that are caused by mutations in X chromosome-linked dystrophin (DMD) are the most common forms in childhood with an estimated incidence of 8.3 or 7.3 per 100,000 male (Wein et al, 2015; Carter et al, 2018). DMD, a severe phenotype clinically, is characterized by a progressive loss of muscle function with onset at age 2 to 5 years, lost ambulation before age 13 years and death at approximately 20 years of age, while BMD shows a mild form with patients being loss of ambulantion after 16 years of age (Mercuri and Muntoni, 2013; Wein et al, 2015; Yiu and Kornberg, 2015). An accurate identification of the causative mutation at the genomic level is critical for genetic counseling of the family, and analysis of genotype–phenotype correlations, as well as a reference for the development of gene therapy
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