title: Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia.
abstract: An inherited predisposition to acute myeloid leukaemia (AML) is exceedingly rare, but the investigation of these families will aid in the delineation of the underlying mechanisms of the more common, sporadic cases. Three AML predisposition genes, RUNX1, CEBPA and GATA2, have been recognised, but the culprit genes in the majority of AML pedigrees remain obscure. We applied a combined strategy of linkage analysis and next-generation sequencing (NGS) technology in an autosomal-dominant AML Chinese family with 11 cases in four generations. A genome-wide linkage scan using a 500K SNP genotyping array was conducted to identify a previously unreported candidate region on 20p13 with a maximum multipoint heterogeneity LOD (HLOD) score of 3.56 (P=0.00005). Targeted NGS within this region and whole-exome sequencing (WES) revealed a missense mutation in TGM6 (RefSeq, NM_198994.2:c.1550T>G, p.(L517W)), which cosegregated with the phenotype in this family, and was absent in 530 healthy controls. The mutated amino acid was located in a highly conserved position, which may be deleterious and affect the activation of TGM6. Our results strongly support the candidacy of TGM6 as a novel familial AML-associated gene.
authors.affiliation: 1] Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, China [2] Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Pan
authors.affiliation: Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Yuan-mao
authors.initials: YM
authors.lastname: Huang
authors.affiliation: Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Xiao-e
authors.initials: XE
authors.lastname: Zhuang
authors.affiliation: Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Dong-feng
authors.initials: DF
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Shi-cheng
authors.initials: SC
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Zhi-shun
authors.initials: ZS
authors.lastname: Zhang
authors.affiliation: Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Sheng-long
authors.initials: SL
authors.lastname: Lin
authors.affiliation: 1] Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, China [2] Union Clinical Medical College, Fujian Medical University, Fuzhou, China.
authors.forename: Shao-yuan
authors.initials: SY
authors.lastname: Wang
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011503:Transglutaminases / Q000235:genetics*
chemical_list: C532876:TGM6 protein, human; D011503:Transglutaminases
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