title: Germline mutations and genotype-phenotype associations in head and neck paraganglioma patients with negative family history in China.
abstract: The aim of this study was to assess the frequency of germline mutations and to explore genotype-phenotype associations in Chinese head and neck paraganglioma (HNPGL) patients without family history. Twenty-six Chinese patients with a diagnosis of HNPGL（14 male and 12 female, respectively）were recruited, who were followed up from 2000 to 2012. Genomic DNA was obtained from resected tumor tissues and peripheral blood samples. Seven genes, Succinate dehydrogenase complex A,B,C,D (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), TMEM127 (transmembrane protein 127) and VHL (Von Hippel-Lindau), were screened by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) was performed to search for potential large deletions or duplications of SDHB, SDHC, SDHD, SDHAF1 and SDHAF2. The total frequency of germline mutations was 30.8% (8/26), including 5 cases with missense mutation p.Met1Ile in SDHD, 1 case with missense mutation p.Tyr216Cys in SDHB, and 1 case with a novel truncation mutation p.Gln44Ter in SDHAF2. MLPA showed one patient with malignant HNPGL had heterozygous deletions of exon1, 2, 3, 7 and 8 in SDHB. Mutations in SDHD were the leading cause of HNPGL in this study. Mutation carriers were younger than non-mutation carriers (p < 0.01) and more likely to suffer from multiple tumors (p = 0.048), especially with mutations in SDHD. The presence of mutation was associated with the development of larger tumors (p = 0.021). This study confirmed that the missense mutation p.Met1Ile at the start codon in SDHD was a hotspot in chinese patients with HNPGLs. We recommend genetic analysis in patients below 45 years, especially SDHD gene.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiaotong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200092, China.
authors.forename: W D
authors.initials: WD
authors.lastname: Zhu
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiaotong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200092, China.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiaotong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200092, China.
authors.forename: Y C
authors.initials: YC
authors.lastname: Chai
authors.affiliation: Ear Institute, Shanghai Jiaotong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200092, China.
authors.forename: X W
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiaotong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200092, China. Electronic address: chendongye@hotmail.com.
authors.forename: D Y
authors.initials: DY
authors.lastname: Chen
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiaotong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 200092, China. Electronic address: wuhao@shsmu.edu.cn.
authors.forename: H
authors.initials: H
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D002681:China; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010235:Paraganglioma / Q000175:diagnosis / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: C491545:SDHD protein, human; D013385:Succinate Dehydrogenase
keywords: Genetic analysis; Germline mutation; Head and neck paraganglioma (HNPGL); Multiplex ligation-dependent probe amplification (MLPA); SDHAF2; SDHB; SDHD