Genotype-phenotype features of germline variants of the TMEM127 pheochromocytoma susceptibility gene: A 10-year update

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 A Liss, Sara Ahmadi, Daniel Katselnik, Enrique Maldonado, Sarimar Agosto Salgado, Camilo Jimenez, Lauren Fishbein, Oksana Hamidi, Tobias Else, Ron LechanArt 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

Producción científica: Articlerevisión exhaustiva

10 Citas (Scopus)


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.

Idioma originalEnglish (US)
Páginas (desde-hasta)E350-E364
PublicaciónJournal of Clinical Endocrinology and Metabolism
EstadoPublished - ene 1 2021

ASJC Scopus subject areas

  • Biochemistry, medical
  • Endocrinology
  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism


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