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Identification of three new variants of SDHx genes in a cohort of Portuguese patients with extra-adrenal paragangliomas

Background: Extra-adrenal paragangliomas (PGL) are rare neoplasms occurring in sporadic and familial forms, the latter mostly in association with germline mutations of SDHB, SDHC or SDHD genes. Aim: Characterize frequency and spectrum of germline mutations among a cohort of Portuguese patients with extra-adrenal PGL. Design: Molecular and clinical data were reviewed on 44 patients referred for genetic testing by a single laboratory. Results: Genetic analysis identified 11 patients with head and neck PGL (30.6%) positive for SDHx gene mutations (6 SDHD, 4 SDHB, 1 SDHC) and 4 patients with abdominal or pelvic PGL (50%) positive for SDHx gene mutations (4 SDHB). Large deletions made up about 20% of the mutations detected. Mutation carriers were younger and more frequently had multiple or malignant PGL than patients without mutations. Only 11 % of the head and neck PGL were secretory. In contrast, 100% of the abdominal or pelvic PGL were secretory. Five patients had a malignant PGL (4 SDHB, 1 apparently sporadic). Three novel mutations were identified: two in the SDHD gene (c.411delT [p.Leu139PhefsX29] and c.371_390del20insGG [p.Ala124_Ala130delinsGly]), one in the SDHB gene (c.49A>G [p.Thr17Ala]). The SDHD variant c.411 delT [p.Leu139PhefsX29] was present in 3 apparently unrelated patients. Molecular genetic testing of 22 relatives disclosed 16 mutation carriers. Conclusions: Genetic analysis identified 15 patients (34.1%) and 16 at-risk individuals (72.7%) positive for SDHx gene mutations. The finding of three novel mutations broadens the mutational profile of the mitochondrial complex II succinate dehydrogenase genes reported in other large European series of patients with paragangliomas. Further studies are needed to clarify whether the high frequency of the SDHD variant c.411 delT [p.Leu139PhefsX29] corresponds to a founder mutation.