Fumarate hydratase gene germline variants and mosaicism associated with pheochromocytoma and paraganglioma

Abstract 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.