Fig. 1 | Genetics in Medicine

Fig. 1

From: Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma

Fig. 1

Krebs cycle metabolite profiling of pheochromocytomas and paragangliomas (PPGLs). a Hierarchical cluster analysis (Ward) of 395 different PPGLs from 391 patients. All possible ratios between eight intermediates (citrate, isocitrate, cis-aconitate, α-ketoglutarate, 2-hydroxyglutarate, succinate, fumarate, malate) of the central carbon metabolism were generated and natural logarithm (LN) transformed. Mutational status (germline and somatic) is shown by color in the left column. Clusters are marked with roman numbers. The Krebs cycle with all measured metabolites is schematically shown; oxaloacetate and succinyl-CoA are not detectable with the used method. 2HG-2 hydroxyglutarate, CIT citrate, cisAC cis-aconitate, FUM fumarate, isoCIT isocitrate, KETO α-ketoglutarate, MAL malate, SUC succinate. b The succinate:fumarate ratio as an indicator for PV in SDHx genes separates cluster I from II. Cut-off defined in ref. 16 marked in blue. c Box plots of 2HG levels with outliers marked as dots. Outliers above the top whisker (the 75th quartile + 1.5× [interquartile range]) were further investigated by next-generation sequencing analysis when the driver PV was unknown (red circle). d Outlier analysis for the fumarate:malate ratio

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