Transcript-Based Diagnosis and Expanded Phenotype of an Intronic Mutation in TPM3 Myopathy

Mol Diagn Ther. 2022 Sep;26(5):561-568. doi: 10.1007/s40291-022-00601-6. Epub 2022 Jul 7.


Introduction: Congenital myopathies are a broad group of inborn muscle disorders caused by a multitude of genetic factors, often characterized by muscle atrophy and hypotonia.

Methods: Clinical studies, imaging, histology, whole-exome sequencing (WES) and muscle tissue RNA studies.

Results: We describe a severe congenital myopathy manifesting at birth with bilateral clubfeet, delayed motor development and hypotonia, becoming evident by 4 months of age. At 3 years of age, the patient had tongue fasciculations, was bedridden, and was chronically ventilated via tracheostomy. Imaging studies demonstrated severe muscle atrophy and, surprisingly, cerebral atrophy; electromyography demonstrated a myasthenic pattern and histological evaluation did not facilitate a definitive diagnosis. Trio WES did not identify a causative variant, except for a non-canonical intronic TPM3 c.118-12G>A variant of uncertain significance. Transcript analysis of muscle tissue from the patient proved the pathogenicity of this homozygous variant, with a 97% reduction in the muscle-specific TPM3.12 transcript.

Discussion: This study broadens the phenotypic spectrum of recessive TPM3 disease, highlighting tongue fasciculations and bilateral clubfoot, as well as possibly-related cerebral atrophy. It also shows the importance of a broad approach to genetic analysis and the utility of RNA-based studies, demonstrating efficacy of early genome and transcriptome queries in facilitating rapid and cost-effective diagnosis of congenital myopathies.

Publication types

  • Case Reports

MeSH terms

  • Fasciculation
  • Humans
  • Muscle Hypotonia*
  • Muscular Atrophy
  • Muscular Diseases*
  • Mutation
  • Phenotype
  • RNA
  • Tropomyosin / genetics


  • TPM3 protein, human
  • Tropomyosin
  • RNA