SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma.
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.
Bayley
Jean-Pierre
JP
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands. j.p.l.bayley@lumc.nl
Kunst
Henricus P M
HP
Cascon
Alberto
A
Sampietro
Maria Lourdes
ML
Gaal
José
J
Korpershoek
Esther
E
Hinojar-Gutierrez
Adolfo
A
Timmers
Henri J L M
HJ
Hoefsloot
Lies H
LH
Hermsen
Mario A
MA
Suárez
Carlos
C
Hussain
A Karim
AK
Vriends
Annette H J T
AH
Hes
Frederik J
FJ
Jansen
Jeroen C
JC
Tops
Carli M
CM
Corssmit
Eleonora P
EP
de Knijff
Peter
P
Lenders
Jacques W M
JW
Cremers
Cor W R J
CW
Devilee
Peter
P
Dinjens
Winand N M
WN
de Krijger
Ronald R
RR
Robledo
Mercedes
M
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
D021122:Protein Subunits; D042963:Electron Transport Complex II; C511268:SDHA protein, human; D013385:Succinate Dehydrogenase