Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation.
BACKGROUND
Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner.


OBJECTIVE
Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL.


METHODS
In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications.


RESULTS
A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation.


CONCLUSIONS
This study supports the value of universal genetic screening for all patients with PC/PGL.
Departments of Endocrinology (R.C., A.G., M.B.), Pathology (M.B.C.), and Clinical Biochemistry (P.O.), Galway University Hospital, Galway, Ireland; and Departments of Endocrinology (A.T., D.O.) and Clinical Biochemistry (C.J.), Cork University Hospital, Cork, Ireland.
Ruth
R
Casey
Aoife
A
Garrahy
Antoinette
A
Tuthill
Domhnall
D
O'Halloran
Caroline
C
Joyce
Mary B
MB
Casey
Paula
P
O'Shea
Marcia
M
Bell
D000310:Adrenal Gland Neoplasms / Q000453:epidemiology / Q000235:genetics*; D000368:Aged; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D010235:Paraganglioma / Q000453:epidemiology / Q000235:genetics*; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics*
D024101:Mitochondrial Proteins; C543341:SDHAF2 protein, human