Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Ann N Y Acad Sci. 2022 Oct;1516(1):262-270. doi: 10.1111/nyas.14866. Epub 2022 Jul 12.
Fumarate hydratase (FH) catalyzes the conversion of fumaric acid to L-malic acid. Heterozygous variants of the human fumarate hydratase gene (FH) predispose to hereditary leiomyomatosis and renal cell cancer and, rarely, pheochromocytoma/paraganglioma (PPGL). No mosaic variant in FH has been reported yet. Using next-generation sequencing, five individuals with FH variants were found in 319 PPGL patients. Immunohistochemistry staining and loss of heterozygosity analysis in tumor tissues were performed to determine the pathogenicity of the variants. Deep targeted sequencing was performed on the peripheral blood DNA of a pheochromocytoma (PCC) patient with uterine leiomyomas. Finally, two of the five variants were found to be pathogenic. A germline variant (c.817G>A, p.Ala273Thr) was found in a patient with a PPGL family history. A mosaic variant (c.206G>A, p.Gly69Asp) with an allelic ratio of 5% in blood DNA was confirmed in the PCC patient with uterine leiomyomas. No metastatic PPGL was observed in the two PPGL patients with FH pathogenic variants. In summary, we report mosaicism in FH and the first PPGL pedigree with an FH pathogenic germline variant. Both germline variants and mosaicism should be taken into account during genetic testing.
延胡索酸水合酶 (FH) 催化延胡索酸转化为 L-苹果酸。人类延胡索酸水合酶基因 (FH) 的杂合变体易患遗传性平滑肌瘤病和肾细胞癌，极少数情况下还会导致嗜铬细胞瘤/副神经节瘤 (PPGL)。目前尚未报道 FH 中的镶嵌变体。通过下一代测序，在 319 例 PPGL 患者中发现了 5 例 FH 变异患者。对肿瘤组织进行免疫组织化学染色和杂合性丢失分析，以确定变异的致病性。对一名患有子宫肌瘤的嗜铬细胞瘤 (PCC) 患者的外周血 DNA 进行深度靶向测序。最后，发现其中两个变体是致病性的。在一名有 PPGL 家族史的患者中发现了一个胚系变异 (c.817G>A, p.Ala273Thr)。在患有子宫肌瘤的 PCC 患者中，在血液 DNA 中发现了一个等位基因比例为 5%的镶嵌变体 (c.206G>A, p.Gly69Asp)。在两个具有 FH 致病性变异的 PPGL 患者中未观察到转移性 PPGL。总之，我们报告了 FH 中的镶嵌现象和首例具有 FH 致病性胚系变异的 PPGL 家族史。在进行基因检测时，应考虑胚系变异和镶嵌现象。
