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

• Published in: Brain (London, England : 1878) Vol. 133; no. 12; pp. 3510 - 3518
• Main Authors: Wang, Jun Ling, Yang, Xu, Xia, Kun, Hu, Zheng Mao, Weng, Ling, Jin, Xin, Jiang, Hong, Zhang, Peng, Shen, Lu, Feng Guo, Ji, 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
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-12-2010
• Subjects: Adult; Age of Onset; Asian Continental Ancestry Group - genetics; Biological and medical sciences; China; Chromosomes, Human, Pair 20 - genetics; Cohort Studies; Databases, Genetic; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA - genetics; Exons; Exons - genetics; Female; Gene Deletion; Gene mapping; Genetic Linkage; Genome-Wide Association Study; Genotype; Humans; Linkage analysis; Male; Medical sciences; Middle Aged; Missense mutation; Mutagenesis, Insertional; Mutation - genetics; Mutation - physiology; Mutation, Missense; Neurodegenerative diseases; Neurology; Pedigree; Point Mutation; Reverse Transcriptase Polymerase Chain Reaction; spinocerebellar ataxia; Spinocerebellar Ataxias - genetics; TGM6; Transglutaminases - genetics; whole-exome sequencing; China; Nervous system diseases; Nucleotide sequence; linkage analysis; Spinocerebellar ataxia; Central nervous system disease; Genetic linkage; Degenerative disease; TGM6; Sequencing; whole-exome sequencing; Genetic disease
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awq323

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.