Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients.
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Calsina Bruna, Currás-Freixes Maria, Buffet Alexandre, Pons Tirso, Contreras Laura, Letón Rocío, Comino-Méndez Iñaki, Remacha Laura, Calatayud María, Obispo Berta, Martin Antoine, Cohen Regis, Richter Susan, Balmaña Judith, Korpershoek Esther, Rapizzi Elena, Deutschbein Timo, Vroonen Laurent, Favier Judith, de Krijger Ronald R, Fassnacht Martin, Beuschlein Felix, Timmers Henri J, Eisenhofer Graeme, Mannelli Massimo, Pacak Karel, Satrústegui Jorgina, Rodríguez-Antona Cristina, Amar Laurence, Cascón Alberto, Dölker Nicole, Gimenez-Roqueplo Anne-Paule, Robledo Mercedes
Аннотация
METHODS: Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach.
RESULTS: Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL.
CONCLUSION: This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes.