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

• Autores: Armaiz Pena, Gustavo; Flores, Shahida K.; Cheng, Zi Ming; Zhang, Xhingyu; Esquivel, Emmanuel; Poullard, Natalie; Vaidyanathan, Anusha; Liu, Qianqian; Michalek, Joel; Santillan Gomez, Alfredo A.; Liss, Michael; Ahmadi, Sara; Katselnik, Daniel; Maldonado, Enrique; Salgado, Sarimar Agosto; Jimenez, Camilo; Fishbein, Lauren; Hamidi, Oksana; Else, Tobias; Lechan, Ron; Tischler, Art S.; Benn, Diana E.; Dwight, Trisha; Clifton Bligh, Rory; Sanso, Elsa Gabriela; Barontini, Marta Beatriz; Vincent, Deepa; Aronin, Neil; Biondi, Bernadette; Koops, Maureen; Bowhay Carnes, Elizabeth; Gimenez Roqueplo, Anne Paule; Alvarez Eslava, Andrea; Bruder, Jan M.; Kitano, Mio; Burnichon, Nelly; Ding, Yanli; Dahia, Patricia L. M.
• Año de publicación: 2021
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: GENOTYPE-PHENOTYPE ASSOCIATION; PARAGANGLIOMA; PHEOCHROMOCYTOMA; TMEM127; TUMOR SUPPRESSOR GENE
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Armaiz Pena, Gustavo. University Of Texas Health Science Center At San Antonio;; Estados Unidos
Fil: Flores, Shahida K.. No especifíca;
Fil: Cheng, Zi Ming. No especifíca;
Fil: Zhang, Xhingyu. No especifíca;
Fil: Esquivel, Emmanuel. No especifíca;
Fil: Poullard, Natalie. No especifíca;
Fil: Vaidyanathan, Anusha. No especifíca;
Fil: Liu, Qianqian. No especifíca;
Fil: Michalek, Joel. No especifíca;
Fil: Santillan Gomez, Alfredo A.. No especifíca;
Fil: Liss, Michael. No especifíca;
Fil: Ahmadi, Sara. No especifíca;
Fil: Katselnik, Daniel. No especifíca;
Fil: Maldonado, Enrique. No especifíca;
Fil: Salgado, Sarimar Agosto. No especifíca;
Fil: Jimenez, Camilo. No especifíca;
Fil: Fishbein, Lauren. No especifíca;
Fil: Hamidi, Oksana. No especifíca;
Fil: Else, Tobias. No especifíca;
Fil: Lechan, Ron. Tufts Medical Center; Estados Unidos
Fil: Tischler, Art S.. Tufts Medical Center; Estados Unidos
Fil: Benn, Diana E.. No especifíca;
Fil: Dwight, Trisha. University of Technology Sydney; Australia
Fil: Clifton Bligh, Rory. University of Technology Sydney; Australia
Fil: Sanso, Elsa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina
Fil: Barontini, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina
Fil: Vincent, Deepa. Massachusetts Institute of Technology; Estados Unidos
Fil: Aronin, Neil. Massachusetts Institute of Technology; Estados Unidos
Fil: Biondi, Bernadette. University of Naples Federico II; Italia
Fil: Koops, Maureen. University of Texas Health San Antonio; Estados Unidos
Fil: Bowhay Carnes, Elizabeth. No especifíca;
Fil: Gimenez Roqueplo, Anne Paule. No especifíca;
Fil: Alvarez Eslava, Andrea. No especifíca;
Fil: Bruder, Jan M.. No especifíca;
Fil: Kitano, Mio. No especifíca;
Fil: Burnichon, Nelly. No especifíca;
Fil: Ding, Yanli. No especifíca;
Fil: Dahia, Patricia L. M.. No especifíca;