Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update
| Autor: | Daniel Katselnik, Yanli Ding, Camilo Jimenez, Michael A. Liss, Bernadette Biondi, Zi Ming Cheng, Tobias Else, Marta Barontini, Nelly Burnichon, Rory Clifton-Bligh, Gustavo Armaiz-Pena, Alfredo A. Santillan-Gomez, Andrea Alvarez-Eslava, Deepa Vincent, Oksana Hamidi, Mio Kitano, Trisha Dwight, Enrique Maldonado, Joel E. Michalek, Diana E. Benn, Emmanuel Esquivel, Gabriela Sanso, Anne Paule Gimenez-Roqueplo, Maureen Koops, Art S. Tischler, Patricia L. M. Dahia, Xhingyu Zhang, Lauren Fishbein, Natalie Poullard, Anusha Vaidyanathan, Qianqian Liu, Shahida K. Flores, Neil Aronin, Ron Lechan, Elizabeth Bowhay-Carnes, Sara Ahmadi, Jan M. Bruder, Sarimar Agosto Salgado |
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| Přispěvatelé: | Armaiz-Pena, G, Flores, Sk, Cheng, Zm, Zhang, X, Esquivel, E, Poullard, N, Vaidyanathan, A, Liu, Q, Michalek, J, Santillan-Gomez, Aa, Liss, M, Ahmadi, S, Katselnik, D, Maldonado, E, Salgado, Sa, Jimenez, C, Fishbein, L, Hamidi, O, Else, T, Lechan, R, Tischler, A, Benn, De, Dwight, T, Clifton-Bligh, R, Sanso, G, Barontini, M, Vincent, D, Aronin, N, Biondi, B, Koops, M, Bowhay-Carnes, E, Gimenez-Roqueplo, Ap, Alvarez-Eslava, A, Bruder, Jm, Kitano, M, Burnichon, N, Ding, Y, Dahia, Plm |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine Oncology Proband medicine.medical_specialty Tumor suppressor gene Endocrinology Diabetes and Metabolism Clinical Biochemistry Adrenal Gland Neoplasms Biochemistry Germline Cohort Studies Pheochromocytoma Young Adult paraganglioma 03 medical and health sciences 0302 clinical medicine Endocrinology Paraganglioma Renal cell carcinoma Internal medicine Databases Genetic medicine Humans Genetic Predisposition to Disease Genetic Testing Family history Online Only Articles Gene Genetic Association Studies Germ-Line Mutation Aged Retrospective Studies Aged 80 and over tumor suppressor gene business.industry Biochemistry (medical) Membrane Proteins Middle Aged medicine.disease pheochromocytoma 030104 developmental biology 030220 oncology & carcinogenesis genotype-phenotype association Female business TMEM127 |
| Zdroj: | J Clin Endocrinol Metab |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/clinem/dgaa741 |
| Popis: | Purpose This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). Design Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Main Outcome Analysis Clinical, genetic, and functional associations were determined. Results The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. Conclusions Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance. |
| Databáze: | OpenAIRE |
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