The Emerging TNNT3 Spectrum: From Distal Arthrogryposis to Congenital Myopathy

Area of Science:

• Genetics
• Molecular Biology
• Neuromuscular Disorders

Background:

• Distal arthrogryposis (DA) comprises nonprogressive congenital muscle disorders affecting distal joints.
• Dominant TNNT3 variants cause severe DA type 2B2, characterized by dysmorphism and limb deformities.
• Previous reports suggested homozygous TNNT3 splicing variants in congenital myopathy, but lacked functional validation.

Purpose of the Study:

• To investigate the TNNT3 genotype-phenotype spectrum in patients with myopathic conditions.
• To functionally characterize novel TNNT3 variants identified in two patients.
• To differentiate TNNT3-related congenital myopathy from DA type 2B2.

Main Methods:

• Exome sequencing to identify genetic variants.
• In silico prediction of variant effects on protein stability.
• Western blot analysis to confirm protein stability changes.
• Biochemical assays to assess protein function and truncation.

Main Results:

• Subject #1 presented with DA and a de novo TNNT3 missense variant (p.Arg63His), predicted and confirmed to affect troponin T3 stability.
• Subject #2 displayed severe congenital myopathy with hypotonia, DA, and dysmorphism, harboring biallelic TNNT3 variants (splicing and stop gain).
• Biochemical analyses demonstrated that the variants in Subject #2 lead to a loss of full-length TNNT3 protein.

Conclusions:

• The TNNT3 genotype-phenotype spectrum is refined and expanded by these findings.
• Recessive TNNT3-related congenital myopathy, caused by biallelic loss-of-function variants, should be recognized as a distinct clinical entity.
• Functional studies are crucial for understanding the impact of TNNT3 variants on muscle function.