Ye Du1, Fangfang Chen2, Jian Zhang3, Zheguang Lin2, Qian Ma2, Guisheng Xu3, Deming Xiao3, Yaoting Gui2, Jun Yang4, Shengxiang Wan5. 1. Medical Research Center, The People's Hospital of Longhua, Shenzhen 518109, China; Guangdong Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Shenzhen 518036, China. 2. Guangdong Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Shenzhen 518036, China. 3. Department of Hand Microsurgery, Peking University Shenzhen Hospital, Shenzhen 518036, China. 4. Department of Radiology, Peking University Shenzhen Hospital, Shenzhen 518036, China. Electronic address: ayjayj_44@163.com. 5. Department of Hand Microsurgery, Peking University Shenzhen Hospital, Shenzhen 518036, China. Electronic address: sxwan620328@sina.com.
Abstract
BACKGROUND: Syndactyly type II (synpolydactyly, SPD) is a rare autosomal dominant inherited disease with higher incomplete penetrance. Currently, several variants in HOXD13 and one deletion in FBLN1 have been associated with SPD. However, the causative variants in several SPD families and their etiological mechanism are still largely unknown. METHODS: Whole exome and PCR-sanger sequencing followed by two-point linkage analysis were performed to identify the pathogenic variant in a six-generation Chinese pedigree. Homology modeling in combination with the RNAi and qRT-PCR experiments was used for revealing the pathogenic mechanism of the TTC30B variant. RESULTS: A six-generation SPD family was reported. The affected subjects in this family had no other clinical malformation beyond SPD. A rare missense variant c.1157C>T [p.Ala375Val] (chr2:178416368, hg19) in TTC30B was demonstrated to be responsible for this SPD family. The modeling structure indicated that the Ala375 was evolutionarily and structurally conserved. The variant p.Ala375Val was predicted to be deleterious for protein structure and/or stability. Two-point linkage analysis resulted in a maximum LOD score of 3.1444 (P = 0.000071). Furthermore, we found that TTC30B was regulated by the Shh signaling pathway and the abnormal expression of TTC30B will affect the activation of the Shh signaling pathway in human retinal pigment epithelial cells. CONCLUSIONS: This study demonstrates for the first time that an IFT (intraflagellar transport) - related gene TTC30B is implicated with SPD.
BACKGROUND:Syndactyly type II (synpolydactyly, SPD) is a rare autosomal dominant inherited disease with higher incomplete penetrance. Currently, several variants in HOXD13 and one deletion in FBLN1 have been associated with SPD. However, the causative variants in several SPD families and their etiological mechanism are still largely unknown. METHODS: Whole exome and PCR-sanger sequencing followed by two-point linkage analysis were performed to identify the pathogenic variant in a six-generation Chinese pedigree. Homology modeling in combination with the RNAi and qRT-PCR experiments was used for revealing the pathogenic mechanism of the TTC30B variant. RESULTS: A six-generation SPD family was reported. The affected subjects in this family had no other clinical malformation beyond SPD. A rare missense variant c.1157C>T [p.Ala375Val] (chr2:178416368, hg19) in TTC30B was demonstrated to be responsible for this SPD family. The modeling structure indicated that the Ala375 was evolutionarily and structurally conserved. The variant p.Ala375Val was predicted to be deleterious for protein structure and/or stability. Two-point linkage analysis resulted in a maximum LOD score of 3.1444 (P = 0.000071). Furthermore, we found that TTC30B was regulated by the Shh signaling pathway and the abnormal expression of TTC30B will affect the activation of the Shh signaling pathway in human retinal pigment epithelial cells. CONCLUSIONS: This study demonstrates for the first time that an IFT (intraflagellar transport) - related gene TTC30B is implicated with SPD.