Prevalence of germline variants in <i>USP8, USP48, CABLES1</i> and <i>PAM</i> in patients with pituitary adenomas

OBJECTIVE: Approximately 5% of pituitary adenomas (PA) are familial, linked to germline variants in AIP, or syndrome-related genes like MEN1. While somatic GNAS and USP8 variants predominate in specific subtypes, PAM and CABLES1 genes are emerging. DESIGN: To investigate the prevalence and clinical significance of germline variants in CABLES1, USP8, USP48, and PAM in patients with PA without established predisposition gene variants. METHODS: We analyzed germline DNA from 346 unrelated patients (mostly diagnosed <35 years) with isolated familial or sporadic PA, using a panel targeting CABLES1, USP8, USP48, and PAM. After excluding 20 with variants in known predisposition genes (MEN1, AIP, CDKN1B, PRKAR1A, SDHB, SDHC, SDHD, GNAS, DICER1), 326 patients remained for analysis. Variant interpretation followed American College of Medical Genetics and Genomics criteria with population frequencies, in silico prediction and segregation analysis. We analyzed tumor DNA from 2 cases to assess loss of heterozygosity (LOH). RESULTS: Uncommon heterozygous germline variants were identified in 30 patients (9.2%), all clinically sporadic. Most variants were classified as benign or of uncertain significance (VUS). Several variants, including USP8 c.104+3A>G, USP48 p.(Pro361Thr), p.(Tyr927Cys) and c.2884 3C>T, and CABLES1 p.(Glu178Lys), were enriched compared with gnomAD frequencies. CABLES1 variants were predominant in macroprolactinomas, USP48 in nonfunctioning PA, and USP8 in prolactinomas and somatotropinomas. No significant genotype-phenotype associations emerged. Familial testing revealed unaffected carriers and LOH was not detected. CONCLUSIONS: No (likely) pathogenic germline variants were identified. While most were benign or VUS, specific variants-most notably in USP48-showed nominal enrichment compared to gnomAD frequencies, which might suggest a potential low-penetrance susceptibility or modifier effect that will require further validation. This work primarily focused on PAM, CABLES1, USP8, and USP48, but other germline or somatic variants may also contribute. Clinical management and genetic counseling should not be guided by benign variants or VUS.

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Journal
European Journal of Endocrinology
Published
2026-04-24
DOI
https://doi.org/10.1093/ejendo/lvag074
Primary Topic
Pituitary Gland Disorders and Treatments
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article
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0.00

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article

Prevalence of germline variants in USP8, USP48, CABLES1 and PAM in patients with pituitary adenomas

Nuria Valdés, Larisa Suárez-Ortega, Maite Aramburu, Maria Dolores Moure et al.
European Journal of Endocrinology
Pituitary Gland Disorders and Treatments
article

Prevalence of germline variants in USP8, USP48, CABLES1 and PAM in patients with pituitary adenomas

Nuria Valdés, Larisa Suárez-Ortega, Maite Aramburu, Maria Dolores Moure, Rodrigo Bancalari, Nancy Portillo, Luís Castaño, Itxaso Rica, Alfonso Soto-Moreno, Gloria Bueno, Paula Casano, J. Guerrero-Fernández, Mauro Boronat, Natividad González-Rivera, María Isabel Hernández, Amaia Vela, C Fernández-Ramos, Ana Rosa Molina, Emilio García-García, I Bernabeu, R García, J C Ferrer, A Carcavilla, G Novoa, M Marbán, P Martin, Candela Baquero, E Artola, C Novo, E Mena, M Clemente, V Cancela, P Bahillo, Idoia Martinez de Lapiscina, M J Dabad, F J Núñez, E Fernández, R Díaz-Torres, E Colino, A C Barreda, C Lamas, M Boronat, E Menéndez, M Chueca, J Linares, F J Acha, M E Dios, L Castro, C Álvarez-Escolá, A Aranaga, A Aguayo, M Araujo, F Cordero, A García-Castaño, G Bueno, P Cabanas, J González-Morla, C Mendoza, C Bezanilla, R Martínez-Salazar, E González-Oliva, E Etxeberria, M S Baez, J I Labarta, I Bilbao, I Diez-López, H Diez, A Aulinas, Alicia Santos, A Escribano, J P López-Siguero, F Nilo, Miguel Paja, V Gallardo, A L Gómez-Gila, B Lecumberri, F Moreno-Macián, B Corredor, R M Álvarez-San Martín, B Huidobro, Y Garcia-Fernandez, N Egaña, D De Sotto, L Manjon, S Leon, A Martínez-Aguayo, J Corcuera, B García-Cuartero, I González-Casado, M C Mayol, Amparo Gonzalez, M González, the Hispanic-Chilean Pituitary Adenomas Collaborative Group, J M Gómez-Vida, S Gómez, G Grau, G Catalán, F Guarda, J Ares, J Barreiro
article en

Abstract

OBJECTIVE: Approximately 5% of pituitary adenomas (PA) are familial, linked to germline variants in AIP, or syndrome-related genes like MEN1. While somatic GNAS and USP8 variants predominate in specific subtypes, PAM and CABLES1 genes are emerging. DESIGN: To investigate the prevalence and clinical significance of germline variants in CABLES1, USP8, USP48, and PAM in patients with PA without established predisposition gene variants. METHODS: We analyzed germline DNA from 346 unrelated patients (mostly diagnosed <35 years) with isolated familial or sporadic PA, using a panel targeting CABLES1, USP8, USP48, and PAM. After excluding 20 with variants in known predisposition genes (MEN1, AIP, CDKN1B, PRKAR1A, SDHB, SDHC, SDHD, GNAS, DICER1), 326 patients remained for analysis. Variant interpretation followed American College of Medical Genetics and Genomics criteria with population frequencies, in silico prediction and segregation analysis. We analyzed tumor DNA from 2 cases to assess loss of heterozygosity (LOH). RESULTS: Uncommon heterozygous germline variants were identified in 30 patients (9.2%), all clinically sporadic. Most variants were classified as benign or of uncertain significance (VUS). Several variants, including USP8 c.104+3A>G, USP48 p.(Pro361Thr), p.(Tyr927Cys) and c.2884 3C>T, and CABLES1 p.(Glu178Lys), were enriched compared with gnomAD frequencies. CABLES1 variants were predominant in macroprolactinomas, USP48 in nonfunctioning PA, and USP8 in prolactinomas and somatotropinomas. No significant genotype-phenotype associations emerged. Familial testing revealed unaffected carriers and LOH was not detected. CONCLUSIONS: No (likely) pathogenic germline variants were identified. While most were benign or VUS, specific variants-most notably in USP48-showed nominal enrichment compared to gnomAD frequencies, which might suggest a potential low-penetrance susceptibility or modifier effect that will require further validation. This work primarily focused on PAM, CABLES1, USP8, and USP48, but other germline or somatic variants may also contribute. Clinical management and genetic counseling should not be guided by benign variants or VUS.

European Journal of EndocrinologyVol. 194(5)
Hospital Sant Joan de Déu Barcelona (ES), University of the Basque Country (ES), Hospital Universitario Insular de Gran Canaria (ES), Hospital Universitario La Paz (ES), Hospital de Sant Pau (ES), Endo Pharmaceuticals (United States) (US), BioCruces Health research Institute (ES), Hospital Universitario Virgen Macarena (ES), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Hospital de Basurto (ES), Biogipuzkoa Health Research Institute (ES), Instituto de Biomedicina de Sevilla (ES), Hospital Clínico Universitario Lozano Blesa (ES), Hospital de Cruces (ES), Donostiako Unibertsitate Ospitalea (ES), Hospital Universitario Virgen del Rocío (ES), Clínica Dávila (CL), Hospital Universitario Severo Ochoa (ES), Instituto de Investigación de Enfermedades Raras (ES), University of Chile (CL)
Instituto de Salud Carlos III, Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa
Openalex Percentile: Top 16%
Pituitary Gland Disorders and Treatments
DOISourceOpenAlex
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