Mutational and clinical spectrum in a cohort of Chinese patients with hereditary nemaline myopathy

Hereditary nemaline myopathy (NM) is one of the most common congenital myopathies with the histopathological findings of nemaline bodies. We used targeted next-generation sequencing to identify causative mutations in 48 NM patients with confirmed myopathological diagnosis, analyze the mutational spectrum and phenotypic features. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) was used to confirm the pathogenic effect of one nebulin (NEB) splicing variant. The results showed that variants were found in five NM-associated genes, including NEB, actin alpha 1 (ACTA1), troponin T1, Kelch repeat and BTB domain-containing 13, and cofilin-2, in 34 (73.9%), 7 (15.2%), 3 (6.5%), 1 (2.2%), and 1 (2.2%) patients, respectively, in a total of 46/48 (95.8%) NM patients. Of the total 64 variants identified, 51 were novel variants including 26 pathogenic, 1 probably pathogenic, and 24 variant of uncertain significance (VUS). Notably, one NEB splicing mutation, c.21417+3A>G causing exon 144 splicing (NM_001164508.1), as confirmed by RT-PCR, was found in 52.9% (18 patients) of NEB variant-carrying patients. Typical congenital NM, the most common clinical subtype (60.4%), was associated with five NM genes. We concluded that hereditary NM showed a highly variable genetic spectrum. NEB was the most frequent causative gene in this Chinese cohort, followed by ACTA1. We found a hotspot splicing mutation in NEB among Chinese cohort.