A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus.

Distal arthrogryposis (DA) is a group of rare, clinically and genetically heterogeneous disorders primarily characterized by congenital contractures of the limb joints. Recently, mutations in genes encoding the fast-twitch skeletal muscle contractile myofibers complex, including troponin I2 (TNNI2), troponin T3 (TNNT3), tropomyosine 2 (TPM2), and embryonic myosin heavy chain 3 (MYH3), and the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1) were confirmed to cause DA1, DA2A, and DA2B. DA2B, or Sheldon-Hall syndrome (SHS; MIM 601680), is intermediate to DA1 and DA2A, or Freeman-Sheldon syndrome (FSS; MIM193700), and shows prominent facial traits. This report describes a Chinese family with SHS over three generations in which all affected individuals showed vertical talus and one demonstrated preauricular tags on the face. Linkage analysis and PCR sequencing revealed a novel substitute mutation at a hot-spot site in TNNT3 (c.187C > T; p.R63C). This mutation was confirmed to cosegregate with the DA phenotype in affected individuals. SIFT and PolyPhen analyses suggest that the mutation is pathogenic. We report this mutation in TNNT3 and speculate that bilateral vertical talus, or severe clubfoot, might be a special characteristic for cases with the TNNT3 R63C mutation.