Identifying Causative Genetic Variants of Pheochromocytoma and Paraganglioma by Next-Generation Sequencing (NGS) in Taiwan
| Autor: | Yuh-Tsyr Chou, 周毓慈 |
|---|---|
| Rok vydání: | 2019 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 107 Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumors arising from adrenal and extra-adrenal chromaffin cells respectively. They mostly present benign, yet show high morbidity and mortality due to the overproduction of catecholamine, which leads to hypertension, arrhythmia and even ischemia stroke. About one thirds of PCC/PGL are caused by germline genetic variants; therefore, here we established a NGS panel to detect possible disease-causing variants. After literature review, we aimed at the top 12 PCC/PGL causative genes (RET, VHL, NF1,FH, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, EGLN1(PHD2)), 10 somatic mutation genes (ARNT(HIF1β), ATRX, BRAF, CSDE1, EPAS1(HIF1α), FGFR1, HRAS, IDH1, SETD2, TP53), 3 fusion genes (BRAF, MAML3, NGFR) and other 7 genes (CDKN2A, H3F3A, IDH2, KMT2D, MDH2C, MERTK, MET) which were reported relative to PCC/PGL. Paired-end reads were generated from Illumina MiSeq platform and analyzed with in-house pipeline (BWA-MEM, Picard SortSam, MarkDuplicates, GATK-BQSR and ANNOVAR). Variants were filtering according to the allele frequencies in gnomAD, ExAC and Taiwan Biobank, and the pathogenicity interpretation were facilitated by disease/gene database, scientific literature and the 2015 ACMG Guidelines. In this study, we sequenced 41 probands and yielded approximately 29% diagnosis rate with identifying 7 different disease-causing variants and several variants of unknown significant (VUS). Among the results, seven unrelated probands carried a same causative variant in SDHD (c.3G>C, p.M1X, NM_003002), which implied a founder mutation in Taiwan. Three different variants of SDHB and SDHD in nine unrelated probands showed metastasis in our study. Variants in TMEM127 and RET showed low allele frequency or absent in population database and predicted to affect protein function deserved further functional study. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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