Gustavo Armaiz-Pena1, Shahida K Flores2, Zi-Ming Cheng2, Xhingyu Zhang2, Emmanuel Esquivel2, Natalie Poullard3, Anusha Vaidyanathan3, Qianqian Liu4, Joel Michalek4, Alfredo A Santillan-Gomez5, Michael Liss6, Sara Ahmadi1, Daniel Katselnik7, Enrique Maldonado1, Sarimar Agosto Salgado8, Camilo Jimenez8, Lauren Fishbein9, Oksana Hamidi10, Tobias Else11, Ron Lechan12, Art S Tischler12, Diana E Benn13, Trisha Dwight13, Rory Clifton-Bligh13, Gabriela Sanso14, Marta Barontini14, Deepa Vincent15, Neil Aronin15, Bernadette Biondi16, Maureen Koops1, Elizabeth Bowhay-Carnes3, Anne-Paule Gimenez-Roqueplo17, Andrea Alvarez-Eslava18, Jan M Bruder1, Mio Kitano3,5, Nelly Burnichon17, Yanli Ding19, Patricia L M Dahia2,3. 1. Division of Endocrinology, Department of Medicine, University of Texas Health San Antonio (UTHSA), San Antonio, Texas. 2. Division of Hematology and Medical Oncology, Department of Medicine, UTHSA, San Antonio, Texas. 3. Mays Cancer Center, UTHSA, San Antonio, Texas. 4. Department of Population Health Sciences, UTHSA, San Antonio, Texas. 5. Division of Surgical Oncology, Department of Surgery, UTHSA, San Antonio, Texas. 6. Department of Urology, UTHSA, San Antonio, Texas. 7. Diabetes and Metabolism Specialists, San Antonio, Texas, USA. 8. Department Endocrine Neoplasia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 9. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado. 10. Division of Endocrinology and Metabolism, UT Southwestern Medical Center, Dallas, Texas. 11. Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. 12. Tufts Medical Center, Boston, Massachusetts. 13. Cancer Genetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia. 14. Center for Endocrinological Investigations (CEDIE), Hospital de Niños R. Gutiérrez, Buenos Aires, C1425EFD Argentina. 15. Division of Endocrinology, University of Massachusetts, Worcester, Massachusetts. 16. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. 17. Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Genetics Department, Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, Paris, France. 18. University Health System, Texas Diabetes Institute, San Antonio, Texas. 19. Department of Pathology, UTHSA, San Antonio, Texas.
Abstract
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.
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.
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