title: SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma.
abstract: BACKGROUND
  Paragangliomas and phaeochromocytomas are neuroendocrine tumours associated frequently with germline mutations of SDHD, SDHC, and SDHB. Previous studies have shown the imprinted SDHAF2 gene to be mutated in a large Dutch kindred with paragangliomas. We aimed to identify SDHAF2 mutation carriers, assess the clinical genetic significance of SDHAF2, and describe the associated clinical phenotype.
  
  
  METHODS
  We undertook a multicentre study in Spain and The Netherlands in 443 apparently sporadic patients with paragangliomas and phaeochromocytomas who did not have mutations in SDHD, SDHC, or SDHB. We analysed DNA of 315 patients for germline mutations of SDHAF2; a subset (n=200) was investigated for gross gene deletions. DNA from a group of 128 tumours was studied for somatic mutations. We also examined a Spanish family with head and neck paragangliomas with a young age of onset for the presence of SDHAF2 mutations, undertook haplotype analysis in this kindred, and assessed their clinical phenotype.
  
  
  RESULTS
  We did not identify any germline or somatic mutations of SDHAF2, and no gross gene deletions were noted in the subset of apparently sporadic patients analysed. Investigation of the Spanish family identified a pathogenic germline DNA mutation of SDHAF2, 232G-->A (Gly78Arg), identical to the Dutch kindred.
  
  
  CONCLUSIONS
  SDHAF2 mutations do not have an important role in phaeochromocytoma and are rare in head and neck paraganglioma. Identification of a second family with the Gly78Arg mutation suggests that this is a crucial residue for the function of SDHAF2. We conclude that SDHAF2 mutation analysis is justified in very young patients with isolated head and neck paraganglioma without mutations in SDHD, SDHC, or SDHB, and in individuals with familial antecedents who are negative for mutations in all other risk genes.
  
  
  BACKGROUND
  Dutch Cancer Society, European Union 6th Framework Program, Fondo Investigaciones Sanitarias, Fundación Mutua Madrileña, and Red Temática de Investigación Cooperativa en Cáncer.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands. j.p.l.bayley@lumc.nl
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bayley
authors.forename: Henricus P M
authors.initials: HP
authors.lastname: Kunst
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascon
authors.forename: Maria Lourdes
authors.initials: ML
authors.lastname: Sampietro
authors.forename: José
authors.initials: J
authors.lastname: Gaal
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Adolfo
authors.initials: A
authors.lastname: Hinojar-Gutierrez
authors.forename: Henri J L M
authors.initials: HJ
authors.lastname: Timmers
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Mario A
authors.initials: MA
authors.lastname: Hermsen
authors.forename: Carlos
authors.initials: C
authors.lastname: Suárez
authors.forename: A Karim
authors.initials: AK
authors.lastname: Hussain
authors.forename: Annette H J T
authors.initials: AH
authors.lastname: Vriends
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Jansen
authors.forename: Carli M
authors.initials: CM
authors.lastname: Tops
authors.forename: Eleonora P
authors.initials: EP
authors.lastname: Corssmit
authors.forename: Peter
authors.initials: P
authors.lastname: de Knijff
authors.forename: Jacques W M
authors.initials: JW
authors.lastname: Lenders
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D017668:Age of Onset; D004252:DNA Mutational Analysis; D042963:Electron Transport Complex II / Q000235:genetics*; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D006258:Head and Neck Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D010235:Paraganglioma / Q000453:epidemiology* / Q000235:genetics*; D010375:Pedigree; D010673:Pheochromocytoma / Q000453:epidemiology* / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D013030:Spain / Q000453:epidemiology; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D021122:Protein Subunits; D042963:Electron Transport Complex II; C511268:SDHA protein, human; D013385:Succinate Dehydrogenase