Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update.

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). Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Clinical, genetic, and functional associations were determined. 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. 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. © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Gustavo Armaiz-Pena, Shahida K Flores, Zi-Ming Cheng, Xhingyu Zhang, Emmanuel Esquivel, Natalie Poullard, Anusha Vaidyanathan, Qianqian Liu, Joel Michalek, Alfredo A Santillan-Gomez, Michael Liss, Sara Ahmadi, Daniel Katselnik, Enrique Maldonado, Sarimar Agosto Salgado, Camilo Jimenez, Lauren Fishbein, Oksana Hamidi, Tobias Else, Ron Lechan, Art S Tischler, Diana E Benn, Trisha Dwight, Rory Clifton-Bligh, Gabriela Sanso, Marta Barontini, Deepa Vincent, Neil Aronin, Bernadette Biondi, Maureen Koops, Elizabeth Bowhay-Carnes, Anne-Paule Gimenez-Roqueplo, Andrea Alvarez-Eslava, Jan M Bruder, Mio Kitano, Nelly Burnichon, Yanli Ding, Patricia L M Dahia. Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update. The Journal of clinical endocrinology and metabolism. 2021 Jan 01;106(1):e350-e364

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PMID: 33051659

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