The Emerging TNNT3 Spectrum: From Distal Arthrogryposis to Congenital Myopathy.

Distal arthrogryposis (DA) is a group of nonprogressive congenital muscular disorders affecting distal limb joints, without concurrent neuromuscular disease. Ten different types of DAs are known, with many different genes involved. Dominant variants in TNNT3 (MIM ∗600692) cause DA type 2B2 (MIM #618435), a severe condition featuring dysmorphism, distal contractures, and deformities of hands and feet. TNNT3 encodes the fast skeletal troponin T, an essential component of the troponin complex that is necessary for calcium-coupled contraction initiation in the striated muscle. Recently, homozygous splicing variants in TNNT3 have been reported in two subjects with a distinctive congenital myopathy, only partially overlapping DA2B2. However, no functional evidence was provided. In this study, we investigated two patients presenting with myopathic conditions at different ends of the TNNT3 spectrum. One subject showed DA, whereas the second displayed a severe congenital myopathy featuring hypotonia, DA, and dysmorphism. Through exome sequencing, we identified the de novo missense change p.(Arg63His) in Subject #1 and biallelic TNNT3 variants in Subject #2, featuring a splicing and a stop gain variant. The p.(Arg63His) was predicted to affect the stability of troponin T3 in silico, and we confirmed this by western blot. Then, employing different biochemical approaches, we showed that the truncated variants identified in #2 (p.[Tyr13∗] and c.480+5G>A) lead to loss of the full-length protein. Our findings refine and expand the TNNT3 genotype-phenotype spectrum, suggesting that recessive TNNT3-related congenital myopathy should be considered a discrete entity caused by biallelic loss-of-function variants.

Copyright © 2025 Nami Altin et al. Human Mutation published by John Wiley & Sons Ltd.