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Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report.

The Journal of clinical endocrinology and metabolism (2014-04-25)
Letizia Canu, Elena Rapizzi, Benedetta Zampetti, Rossella Fucci, Gabriella Nesi, Susan Richter, Nan Qin, Valentino Giachè, Carlo Bergamini, Gabriele Parenti, Andrea Valeri, Tonino Ercolino, Graeme Eisenhofer, Massimo Mannelli
ABSTRACT

About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism. We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation. We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry. Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism. Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-SDHB antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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Anti-SDHB antibody produced in rabbit, affinity isolated antibody
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Anti-SDHB antibody produced in goat, affinity isolated antibody, buffered aqueous solution
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Monoclonal Anti-SDHB antibody produced in mouse, Prestige Antibodies® Powered by Atlas Antibodies, clone CL0349, purified immunoglobulin, buffered aqueous glycerol solution
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Monoclonal Anti-SDHB antibody produced in mouse, Prestige Antibodies® Powered by Atlas Antibodies, clone CL0347, purified immunoglobulin, buffered aqueous glycerol solution