The analysis of genetic variants in nine patients with nemaline myopathy: implications for diagnosis and genetic counseling

Nemaline myopathy (NM) is a rare and hereditary myopathy caused by the fact that several related genes have been identified, thus exhibiting significant clinical and genetic heterogeneity. This study retrospectively analyzed 9 patients with NM. We utilized WES testing and bioinformatics analysis was performed on 9 families. Normal Mode Analysis (NMA) was used to evaluate the impact of missense variants in the NEB gene on the thermodynamic stability of the nebulin protein. The WES results revealed 17 variants in the TPM3 , NEB , and ACTA1 genes in the 9 patients. According to the variant classification criteria published by the American College of Medical Genetics and Genomics (ACMG), approximately two-thirds of the variants were classified as pathogenic or likely pathogenic, while the remaining variants were classified as of uncertain significance. Meanwhile, our coarse-grained network meta-analysis of missense variants in the NEB gene showed that, compared with the other two missense variants, the c.9146T > G (p. Ile3049Ser) variant exhibited a significantly higher entropy value within the protein’s thermodynamic range, which may lead to protein instability. This study provides valuable insights and approaches for the diagnosis, prognosis, and genetic counseling of NM. By reviewing these cases, we hope to enrich the existing NM knowledge base.