Germline Mutations And Genotype-phenotype Associations In Head And Neck Paraganglioma Patients With Negative Family History In China

Objective: To assess the frequency of germline mutations and to explore genotype-phenotype associations in Chinese head and neck paraganglioma(HNPGL)patients without family history.Methods: 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 protein127)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.Results: The total frequency of germline mutations was 30.8%(8/26),including 5 cases with missense mutation p.Met1 Ile in SDHD,1 case with missense mutation p.Tyr216 Cys in SDHB,and 1 case with a novel truncation mutation p.Gln44 Ter 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).Conclusion: In conclusion,HNPGLs are characterised by the development of multiple,early onset and larger paragangliomas as a result of germline mutations in the SDHx genes.This study confirm that p.Met1Ile(c.3G>C)in SDHD,a missense mutation at the start codon of the gene,is a hotspot in chinese HNPGL patients.The genetic screening of candidate gene,especially SDHD gene,has a valuable role in the management of patients with HNPGLs below 45 years.