A Large Deletion Affecting TPM3, Causing Severe Nemaline Myopathy.

Area of Science:

• Genetics
• Molecular Biology
• Neuromuscular Disorders

Background:

• Nemaline myopathy (NM) is often caused by variants in the TPM3 gene, typically point mutations.
• Previously identified TPM3 variants include missense, nonsense, and splice-site mutations.

Purpose of the Study:

• To identify the disease-causing gene in a patient with suspected nemaline myopathy.
• To confirm the nemaline myopathy diagnosis and investigate the genetic basis.

Main Methods:

• Utilized a nemaline myopathy comparative genomic hybridization (NM-CGH) array to detect large genomic aberrations.
• Employed whole-genome array-CGH, dHPLC, Sanger sequencing, and whole-exome sequencing for comprehensive mutation analysis.
• Conducted histopathological examination of muscle biopsy samples.

Main Results:

• Identified the first large (17-21 kb) deletion in the TPM3 gene using the NM-CGH array.
• The homozygous deletion encompassed exons 1a and 2b and the promoter of the TPM3 isoform encoding Tpm3.12st.
• The patient presented with severe symptoms including profound weakness and feeding difficulties, leading to death at 17.5 months. Muscle biopsy revealed characteristic features of nemaline myopathy.

Conclusions:

• This study reports a rare copy number variation (large deletion) in the TPM3 gene as a cause of nemaline myopathy.
• Suggests that large deletions or duplications in NM-associated genes like TPM3 and NEB, while rare, are possible causes of the disorder.