A novel pathogenic variant c.44A > G (p. Asp15Gly) in TPM3 causing the phenotype of CMYP4A: A case report

Abstract

Tropomyosin 3 (TPM3) encodes the slow α-tropomyosin isoform (Tpm3.12), an actin-binding protein that plays a critical role in the regulation of muscle contraction. Mutations in TPM3 are associated with the characteristic features of congenital myopathy (CM).

A 15-year-old boy had a history of developmental delay, he had long narrow face with a myopathic facial appearance, mild scoliosis of the spine, grade IV muscle strength in the extremities, low muscle tone, absent bilateral knee tendon reflexes, and negative pathological findings. MRI revealed fat infiltration in the leg muscles and the surrounding muscle spaces. Muscle biopsy indicated muscle fiber type disproportion. A novel heterozygous mutation of unknown significance, c.44A > G(p.Asp15Gly), in TPM3 gene was identified. This mutation was confirmed to be de novo and was not present in the proband's parents or sister. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic. PyMOL software analysis indicated that the variant affects the intermolecular interactions within the Tpm3.12. Interestingly, we also found that the patient has been mouth-breathing since infancy, along with a skeletal open bite. This phenotype that has not been previously described.

Our study expands the mutation spectrum of TPM3 and offers valuable insights for the clinical diagnosis and genetic counseling of children with CMYP4A.