Genetic Diagnosis and Individualized Intervention Through Next-generation Sequencing in Pre-symptomatic, Atypical, or Mildly Symptomatic Cases

Background: Conventional diagnoses of neuromuscular disorders (NMD) are insufficient for patients with absent or atypical symptoms. However, genetic diagnosis provides individualized insights for treatment and management. This study aimed to establish definitive diagnoses using next-generation sequencing (NGS) and to implement clinical management. This study also examines important considerations in NGS analyses. Methods: Targeted sequencing with the NMD panel was performed for 21 undiagnosed cases, followed by comprehensive NGS analysis using the clinical exome sequencing panel. Results: A girl with fukutin (FKTN) pathogenic variants and a boy with a dystrophin (DMD) pathogenic variant were genetically diagnosed with dilated cardiomyopathy (DCM) and underwent strict management by pediatric cardiologists. The oldest reported case of a bcl-2-associated athanogene-3 (BAG3) pathogenic variant was diagnosed with myofibrillar myopathy 6. A man with mild symptoms was diagnosed with congenital myasthenic syndrome 7A due to a synaptotagmin 2 (SYT2) pathogenic variant, which showed potential for treatment. A patient with nemaline myopathy 2, caused by nebulin (NEB) pathogenic variants, is under respiratory monitoring. Conclusions: In presymptomatic or atypical cases, a definitive diagnosis was achieved using clinical information, conventional testing, and NGS analysis, and specific clinical management strategies were developed. Individualized interventions, including revisiting conventional testing based on NGS findings, are useful.