ECE2023 Poster Presentations Adrenal and Cardiovascular Endocrinology (72 abstracts)
Description of 38 novel ARMC5 variants and review of the literature: the updated mutational landscape of ARMC5 in Bilateral Macronodular Adrenocortical Disease
Lucas Bouys 1 , Anna Vaczlavik 1 , Isadora Pontes Cavalcante 1 , Florian Violon 1 , Anne Jouinot 1 , Annabel Berthon 1 , Patricia Vaduva 1 , Stéphanie Espiard 2 , Karine Perlemoine 1 , Peter Kamenicky 3 , Marie-Christine Vantyghem 2 , Antoine Tabarin 4 , Gerald Raverot 5 , Cristina Ronchi 6 , Ulrich Dischinger 7 , Martin Reincke 8 , Maria Candida Barisson Villares Fragoso 9 , Constantine Stratakis 10 , Marie-Odile North 11 , Eric Pasmant 1 , Bruno Ragazzon 1 & Jerome Bertherat 1
1Université Paris Cité, Paris, France; 2CHRU Lille, Lille, France; 3Université Paris Saclay, Paris, France; 4CHU Bordeaux, Bordeaux, France; 5Hospices Civils de Lyon, Lyon, France; 6University of Birmingham, Birmingham, United Kingdom; 7University Hospital of Würzburg, Würzburg, Germany; 8Klinikum der Universität München, Munich, Germany; 9University of Sao Paulo, Sao Paulo, Brazil; 10National Institute of Health, Bethesda, United States; 11Hôpital Cochin, Paris, France
Introduction: Bilateral Macronodular Adrenocortical Disease (BMAD) is a rare cause of Cushing syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 have been described by our group 10 years ago and are responsible for 20-25% of apparently sporadic BMAD cases and 80% of familial presentations. ARMC5 patients present with a more pronounced phenotype than wild-type patients, in terms of cortisol excess, number of nodules, and prevalence of Cushing’s complications. ARMC5 screening is now routinely performed for BMAD patients and families.
Methods: Based on literature review and on our own observations, this study aims to give an overview of both published and unpublished ARMC5 genetic alterations and to compile the available evidence to discriminate pathogenic from benign variants.
Results: 135 different germline variants (97 previously reported and 38 novels from our center) are identified in 212 unrelated patients, including 62 (46%) missense substitutions, 39 (29%) frameshift deletions or insertions, 24 (18%) nonsense variants, 4 (3%) affecting splice sites, 4 (3%) in-frame variants and 2 (1%) large deletions. The variants are spread on the entire coding sequence of the gene and most of them are private, with few recurrent hotspots (only 6 variants have been found in 5 or more different index patients). The pathogenic nature of ARMC5 variants is established according to the recommendations of the American College of Medical Genetics, on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing. Indeed, in addition to the germline events, somatic 16p loss-of-heterozygosity and 70 different somatic events are described, leading to a bi-allelic inactivation of the gene, in accordance with a tumor suppressor gene model. Besides BMAD, the presence of a germline ARMC5 variant has also been associated with the occurrence of meningiomas in 9 patients, with the demonstration of a second somatic event in 2 of them.
Conclusion: This work is the first extensive analysis of all the ARMC5 genetic alterations reported so far in the literature with the addition of 38 unpublished variants identified in our center. A total of 196 different ARMC5 alterations are reported here: 135 germline and 70 somatic variants (9 reported both as germline and somatic alterations). The present study is an important source of information and provides a list of variants, classified upon their pathogenic nature, which could help clinicians and geneticists to discriminate pathogenic from benign variants.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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