OR29-5 New Insights into the Genotype/Phenotype Profile of TMEM127 Germline Mutations

Abstract: Pheochromocytomas/paragangliomas (PHEOs/PGLs) are frequently heritable catecholamine-secreting, neuroendocrine tumors. More than 15 distinct genes cause PHEO/PGL predisposition, including the TMEM127 tumor suppressor gene, a transmembrane protein of unknown function. The clinical spectrum, disease severity and risk of other tumors has not been well established in TMEM127-associated disease. This information is critically important for risk assessment and follow up of probands and mutation-carrier relatives. Goal: The objective of this study is to identify clinical and genetic features of patients with germline TMEM127 mutations and begin to delineate genotype-phenotype associations of relevance for clinical and follow up surveillance. Methods: Demographic and clinical data, including tumor type and location, family history, age at diagnosis, plasma and/or urine catecholamine and/or metanephrine levels, and mutation status were obtained from medical records and/or literature of patients identified with TMEM127 gene nonsynonymous variants. Results: 97 index patients (28 males/50 females/19 unreported) were identified with a germline TMEM127 variant. The most common clinical presentation was PHEO (n=72, 74.2%), followed by PGL (n=6, 6.1%) and renal cell carcinoma (RCC n=5, 5.1%). In addition, three patients presented with both PHEO and PGL (3%), two of which were head and neck PGL, and three other patients had combined PHEO and RCC (3%). The median age at diagnosis was 43.8 years (range, 9 months to 80 years). Twenty-five patients had multicentric presentation, mostly due to bilateral pheochromocytoma (20/25 patients, 80%). Familial history of PHEO/PGL was present in 13 patients and five individuals developed metastatic PHEO. Of those with available biochemical data, tumors secreted predominantly epinephrine (n=14/26, 53.8%), although norepinephrine- (n=2) and dopamine- (n=1) secreting tumors were also detected, and one tumor was non-secreting. In total, 70 distinct variants were identified. Most had a single occurrence (n= 56/70 80%), but 14 variants were detected more than once (2-7 times). Most mutations led to a truncated product including indels, splice site or nonsense variants (56.3%), while 43.6.% were missense. Approximately half of the missense mutations occurred within transmembrane domains. Conclusion: The most common presentation of TMEM127-associated disease is a single PHEO in patients older than 40y, similar to sporadic disease, as previously suggested. However, the frequency of PGLs and malignant disease is higher, while penetrance is lower, than previously reported. This information will be relevant for clinical surveillance strategies for affected individuals and their high-risk relatives.