Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation
Ruth Casey1, Aoife Garrahy, Antoinette Tuthill
1Departments 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.
Context:
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.
Conclusion:
This study supports the value of universal genetic screening for all patients with PC/PGL.
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