The link between alterations in the tricarboxylic acid (TCA) cycle and pheochromocytoma/paraganglioma (PCC/PGL) development was first identified in 2000 when Baysal et al found mutations in SDHD in patients with the disease. Since then, mutations in seven additional genes related to the TCA cycle (SDHA, SDHB, SDHC, SDHAF2, IDH1, FH and MDH2) have been reported, which stresses the crucial role of this pathway in PCC/PGL development. Several more recent studies have identified a CpG island methylator phenotype (CIMP)-profile associated with the presence of TCA gene mutations in PCC/PGL, caused by impaired histone demethylation and 5-mC hydroxylation (5-hmC) due to the enzymatic inhibition of multiple α-KG-dependent dioxygenases. These alterations are due to the accumulation of metabolites, such as succinate, fumarate and D-2-hydroxyglutarate, in tumors carrying genetic alterations in the previously mentioned TCA cycle-related genes. In addition, tumors showing this phenotype, but no alterations in the known predisposing genes could harbor mutations in other TCA-related genes. Here we use downregulation and methylation of RBP1, as a marker of a hypermethylation profile, to select a series of PCCs and PGLs for targeted exome sequencing of a panel of TCA cycle-related genes. Methylation profiling, metabolite assessment and additional functional analyses were also performed in selected cases. One of the eleven tumors selected was found to carry a known cancer-predisposing somatic mutation in IDH1. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple PCCs and GIST. Finally, two rare germline variants (one activating and the other one truncating) in new susceptibility genes were found in two tumors showing a CIMP-like profile and altered metabolites ratios. This study further attests to the relevance of the TCA cycle in the development of PCC/PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol.