A novel deletion in TNNI2 causes distal arthrogryposis in a large Chinese family with marked variability of expression

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Distal arthrogryposis (DA) is composed of a group of clinically and genetically heterogeneous disorders, characterized by multiple congenital contractures of the limbs. Point mutations in three genes encoding contractile fast-twitch myofibers, TPM2, TNNI2 and TNNT3, were recently identified in DA type 1 (DA1; MIM 108120) and DA type 2B (DA2B; MIM 601680). We have described a large Chinese DA family in which different individuals had phenotypes similar to DA1 or DA2B. To map the disease locus in this family, two-point linkage analysis was first performed using microsatellite markers selected from the genomic regions close to the TPM2, TNNI2/TNNT3 and TNNC2 genes. A positive LOD score of 3.61 at theta = 0 was obtained with the marker close to the TNNI2/TNNT3 genes, corresponding to the genetic mapping site of DA2B. Direct sequencing of the PCR-amplified DNA fragment spanning exon 8 of the TNNI2 gene showed a heterozygous deletion, c.523_525delAAG (p.K175del), in the proband. This novel mutation was confirmed to cosegregate with the DA phenotype in affected individuals but not detected in all unaffected individuals of the family and not in 50 healthy controls. In summary, we have found a novel TNNI2 mutation in a Chinese family with DA2B. Our work represents the first report on the link between TNNI2 and the DA phenotype in Chinese.