Next-generation sequencing approaches for neuromuscular disorders

Hwang Joo-Yeon, Ahn Younjhin
Division of Rare Diseases, Center for Biomedical Sciences, KNIH, KCDC

Inherited primary myopathy with onset at an early age exhibits genetic heterogeneity and clinical variability, and can be sub-classified into muscular dystrophy, congenital myopathy, mitochondrial myopathy, and metabolic myopathy. The common features involve abnormalities of the muscle cell structure and metabolism that contribute to muscle weakness and dysfunction.
Rapid improvements in massively parallel sequencing platforms have led to important opportunities for identifying clear-cut genotype-phenotype correlations in heterogeneous hereditary conditions. To date, mutations in more than 100 different genes have been identified in hereditary primary myopathies. However, molecular genetic diagnostics are complicated by the overlapping phenotypes associated with frequently mutated genes such as TTN reported in public exomes databases.
Recently, the Korea National Institute of Health (KNIH) has been focused on uncovering and identifying disease-causing variants through a family-based whole-exome sequencing approach. Integrative functional enrichment analyses have provided valuable information for gaining a better understanding and interpretation of novel variants, including functional annotations of structural variation and genetic regulation. We expect that our findings will provide additional insight into phenotypic convergence in the diagnosis of muscle disorders.

Keywords: Whole exome sequencing, Genotype-phenotype correlation, Trio-CES, Myopathy, Neuromuscular disorders