title: Identification of three new variants of SDHx genes in a cohort of Portuguese patients with extra-adrenal paragangliomas.
abstract: BACKGROUND
  Extra-adrenal paragangliomas (PGL) are rare neoplasms occurring in sporadic and familial forms, the latter mostly in association with germline mutations of SD- HB, SDHC or SDHD genes.
  
  
  OBJECTIVE
  Characterize frequency and spectrum of germline mutations among a cohort of Portuguese patients with extra-adrenal PGL.
  
  
  METHODS
  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 SD- Hx 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.411delT [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.411delT [p.Leu139PhefsX29] corresponds to a founder mutation.
authors.affiliation: Centro de Investigação de Patobiologia Molecular (CIPM), Lisbon, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Domingues
authors.forename: P
authors.initials: P
authors.lastname: Montalvão
authors.forename: M
authors.initials: M
authors.lastname: Magalhães
authors.forename: R
authors.initials: R
authors.lastname: Santos
authors.forename: L
authors.initials: L
authors.lastname: Duarte
authors.forename: M J
authors.initials: MJ
authors.lastname: Bugalho
mesh_terms: D000008:Abdominal Neoplasms / Q000201:enzymology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010236:Paraganglioma, Extra-Adrenal / Q000201:enzymology / Q000235:genetics*; D011174:Portugal; D017422:Sequence Analysis, DNA; D013385:Succinate Dehydrogenase / Q000235:genetics*; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D013385:Succinate Dehydrogenase