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.

中文翻译：

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与嗜铬细胞瘤和副神经节瘤相关的富马酸水合酶基因种系变异和嵌合体

富马酸水合酶 (FH) 催化富马酸转化为L-苹果酸。人类富马酸水合酶基因 ( FH ) 的杂合变体易患遗传性平滑肌瘤病和肾细胞癌，罕见情况下易患嗜铬细胞瘤/副神经节瘤 (PPGL)。尚未报道FH中的马赛克变体。使用二代测序，五名FH患者在 319 名 PPGL 患者中发现了变异。在肿瘤组织中进行免疫组织化学染色和杂合性丢失分析以确定变异体的致病性。对患有子宫平滑肌瘤的嗜铬细胞瘤 (PCC) 患者的外周血 DNA 进行了深度靶向测序。最后，发现五个变体中的两个具有致病性。在具有 PPGL 家族史的患者中发现了胚系变异体 (c.817G>A, p.Ala273Thr)。在患有子宫平滑肌瘤的 PCC 患者中证实了血液 DNA 中等位基因比率为 5% 的镶嵌变异体 (c.206G>A, p.Gly69Asp)。在两名具有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中的镶嵌现象和第一个具有FH的 PPGL 谱系致病性种系变异。在基因检测过程中，应同时考虑种系变异和嵌合现象。