Key result
A large homozygous deletion (17-21 kb) in the TPM3 gene was identified as the cause of severe nemaline myopathy in an infant, representing the first such copy number variation found in an NM gene other than NEB.
Case Report (n=1)
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This is the first report of a large deletion in the TPM3 gene causing severe nemaline myopathy, expanding the known genetic mechanisms of the disease.
BACKGROUND AND OBJECTIVES: Nemaline myopathy may be caused by pathogenic variants in the TPM3 gene and is then called NEM1. All previously identified disease-causing variants are point mutations including missense, nonsense and splice-site variants. The aim of the study was to identify the disease-causing gene in this patient and verify the NM diagnosis. METHODS: Mutation analysis methods include our self-designed nemaline myopathy array, The Nemaline Myopathy Comparative Genomic Hybridisation Array (NM-CGH array), whole-genome array-CGH, dHPLC, Sanger sequencing and whole-exome sequencing. The diagnostic muscle biopsy was investigated further by routine histopathological methods. RESULTS: We present here the first large (17-21 kb) aberration in the α-tropomyosinslow gene (TPM3), identified using the NM-CGH array. This homozygous deletion removes the exons 1a and 2b as well as the promoter of the TPM3 isoform encoding Tpm3.12st. The severe phenotype included paucity of movement, proximal and axial weakness and feeding difficulties requiring nasogastric tube feeding. The infant died at the age of 17.5 months. Muscle biopsy showed variation in fibre size and rods in a population of hypotrophic muscle fibres expressing slow myosin, often with internal nuclei, and abnormal immunolabelling revealing many hybrid fibres. CONCLUSIONS: This is the only copy number variation we have identified in any NM gene other than nebulin (NEB), suggesting that large deletions or duplications in these genes are very rare, yet possible, causes of NM.
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Kiiski et al. (2015) conducted a case report in Nemaline myopathy (n=1). Homozygous deletion in the TPM3 gene was evaluated on Identification of disease-causing gene and verification of NM diagnosis. A large homozygous deletion (17-21 kb) in the TPM3 gene was identified as the cause of severe nemaline myopathy in an infant, representing the first such copy number variation found in an NM gene other than NEB.
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