TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing

Wang, Jun Ling, Yang, Xu, Xia, Kun, Hu, Zheng Mao, Weng, Ling, Jin, Xin, Jiang, Hong, Zhang, Peng, Shen, Lu, Guo, Ji Feng, Li, Nan, Li, Ying Rui, Lei, Li Fang, Zhou, Jie, Du, Juan, Zhou, Ya Fang, Pan, Qian, Wang, Jian, Wang, Jun, Li, Rui Qiang and Tang, Bei Sha (2010) TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain, 133 12: 3510-3518. doi:10.1093/brain/awq323

Author Wang, Jun Ling
Yang, Xu
Xia, Kun
Hu, Zheng Mao
Weng, Ling
Jin, Xin
Jiang, Hong
Zhang, Peng
Shen, Lu
Guo, Ji Feng
Li, Nan
Li, Ying Rui
Lei, Li Fang
Zhou, Jie
Du, Juan
Zhou, Ya Fang
Pan, Qian
Wang, Jian
Wang, Jun
Li, Rui Qiang
Tang, Bei Sha
Title TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing
Journal name Brain   Check publisher's open access policy
ISSN 0006-8950
Publication date 2010
Sub-type Article (original research)
DOI 10.1093/brain/awq323
Volume 133
Issue 12
Start page 3510
End page 3518
Total pages 9
Language eng
Subject 2728 Clinical Neurology
Abstract Autosomal-dominant spinocerebellar ataxias constitute a large, heterogeneous group of progressive neurodegenerative diseases with multiple types. To date, classical genetic studies have revealed 31 distinct genetic forms of spinocerebellar ataxias and identified 19 causative genes. Traditional positional cloning strategies, however, have limitations for finding causative genes of rare Mendelian disorders. Here, we used a combined strategy of exome sequencing and linkage analysis to identify a novel spinocerebellar ataxia causative gene, TGM6. We sequenced the whole exome of four patients in a Chinese four-generation spinocerebellar ataxia family and identified a missense mutation, C.1550T-G transition (L517W), in exon 10 of TGM6. This change is at a highly conserved position, is predicted to have a functional impact, and completely cosegregated with the phenotype. The exome results were validated using linkage analysis. The mutation we identified using exome sequencing was located in the same region (20p13-12.2) as that identified by linkage analysis, which cross-validated TGM6 as the causative spinocerebellar ataxia gene in this family. We also showed that the causative gene could be mapped by a combined method of linkage analysis and sequencing of one sample from the family. We further confirmed our finding by identifying another missense mutation C.980A-G transition (D327G) in exon seven of TGM6 in an additional spinocerebellar ataxia family, which also cosegregated with the phenotype. Both mutations were absent in 500 normal unaffected individuals of matched geographical ancestry. The finding of TGM6 as a novel causative gene of spinocerebellar ataxia illustrates whole-exome sequencing of affected individuals from one family as an effective and cost efficient method for mapping genes of rare Mendelian disorders and the use of linkage analysis and exome sequencing for further improving efficiency.
Keyword Linkage analysis
Spinocerebellar ataxia
Whole-exome sequencing
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Scopus Import
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