The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update
Abstract Background Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing’s syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20–25% of apparently sporadic PBMAH cases and 80% o...
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2025-02-01
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| author | Lucas Bouys Anna Vaczlavik Isadora P. Cavalcante Florian Violon Anne Jouinot Annabel Berthon Patricia Vaduva Stéphanie Espiard Karine Perlemoine Peter Kamenicky Marie-Christine Vantyghem Antoine Tabarin Gérald Raverot Cristina L. Ronchi Ulrich Dischinger Martin Reincke Maria C. Fragoso Constantine A. Stratakis Albain Chansavang Eric Pasmant Bruno Ragazzon Jérôme Bertherat for the COMETE and ENSAT Networks |
| author_facet | Lucas Bouys Anna Vaczlavik Isadora P. Cavalcante Florian Violon Anne Jouinot Annabel Berthon Patricia Vaduva Stéphanie Espiard Karine Perlemoine Peter Kamenicky Marie-Christine Vantyghem Antoine Tabarin Gérald Raverot Cristina L. Ronchi Ulrich Dischinger Martin Reincke Maria C. Fragoso Constantine A. Stratakis Albain Chansavang Eric Pasmant Bruno Ragazzon Jérôme Bertherat for the COMETE and ENSAT Networks |
| author_sort | Lucas Bouys |
| collection | DOAJ |
| description | Abstract Background Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing’s syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20–25% of apparently sporadic PBMAH cases and 80% of familial presentations. ARMC5 screening is now routinely performed for PBMAH patients and families. Based on literature review and own observation, this study aims to give an overview of both published and unpublished ARMC5 genetic alterations and to compile the available evidence to discriminate pathogenic from benign variants.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 146 different germline variants (110 previously published and 36 novel) are identified, including 46% missense substitutions, 45% truncating variants, 3% affecting splice sites, 4% in-frame variants and 2% large deletions. In addition to the germline events, somatic 16p loss-of-heterozygosity and 104 different somatic events are described. The pathogenicity of ARMC5 variants is established on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing. Conclusions This is the first extensive review of ARMC5 pathogenic variants. It shows that they are spread on the whole coding sequence. This is a valuable resource for genetic investigations of PBMAH and will help the interpretation of new missense substitutions that are continuously identified. |
| format | Article |
| id | doaj-art-326ecc2072314c7e8d6b408921244d14 |
| institution | Kabale University |
| issn | 1750-1172 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-326ecc2072314c7e8d6b408921244d142025-02-09T12:54:02ZengBMCOrphanet Journal of Rare Diseases1750-11722025-02-0120112110.1186/s13023-025-03554-1The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an updateLucas Bouys0Anna Vaczlavik1Isadora P. Cavalcante2Florian Violon3Anne Jouinot4Annabel Berthon5Patricia Vaduva6Stéphanie Espiard7Karine Perlemoine8Peter Kamenicky9Marie-Christine Vantyghem10Antoine Tabarin11Gérald Raverot12Cristina L. Ronchi13Ulrich Dischinger14Martin Reincke15Maria C. Fragoso16Constantine A. Stratakis17Albain Chansavang18Eric Pasmant19Bruno Ragazzon20Jérôme Bertherat21for the COMETE and ENSAT NetworksUniversité Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Department of Endocrinology and Reproduction, Reference Center for Rare Pituitary Diseases, Hôpital Bicêtre, Assistance Publique Hôpitaux de ParisDepartment of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU BordeauxDepartment of Endocrinology, Groupement Hospitalier Est, Hospices Civils de LyonInstitute of Metabolism and System Research, University of BirminghamDivision of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of WürzburgMedizinische Klinik und Poliklinik IV, Klinikum der Universität MünchenDepartment of Endocrinology, Adrenal Unit, University of Sao PauloSection on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH)Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104Abstract Background Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing’s syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20–25% of apparently sporadic PBMAH cases and 80% of familial presentations. ARMC5 screening is now routinely performed for PBMAH patients and families. Based on literature review and own observation, 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 146 different germline variants (110 previously published and 36 novel) are identified, including 46% missense substitutions, 45% truncating variants, 3% affecting splice sites, 4% in-frame variants and 2% large deletions. In addition to the germline events, somatic 16p loss-of-heterozygosity and 104 different somatic events are described. The pathogenicity of ARMC5 variants is established on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing. Conclusions This is the first extensive review of ARMC5 pathogenic variants. It shows that they are spread on the whole coding sequence. This is a valuable resource for genetic investigations of PBMAH and will help the interpretation of new missense substitutions that are continuously identified.https://doi.org/10.1186/s13023-025-03554-1ARMC5GeneticsAdrenal glandCushing’s syndromePrimary Bilateral Macronodular Adrenal HyperplasiaCortisol |
| spellingShingle | Lucas Bouys Anna Vaczlavik Isadora P. Cavalcante Florian Violon Anne Jouinot Annabel Berthon Patricia Vaduva Stéphanie Espiard Karine Perlemoine Peter Kamenicky Marie-Christine Vantyghem Antoine Tabarin Gérald Raverot Cristina L. Ronchi Ulrich Dischinger Martin Reincke Maria C. Fragoso Constantine A. Stratakis Albain Chansavang Eric Pasmant Bruno Ragazzon Jérôme Bertherat for the COMETE and ENSAT Networks The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update Orphanet Journal of Rare Diseases ARMC5 Genetics Adrenal gland Cushing’s syndrome Primary Bilateral Macronodular Adrenal Hyperplasia Cortisol |
| title | The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update |
| title_full | The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update |
| title_fullStr | The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update |
| title_full_unstemmed | The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update |
| title_short | The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update |
| title_sort | mutational landscape of armc5 in primary bilateral macronodular adrenal hyperplasia an update |
| topic | ARMC5 Genetics Adrenal gland Cushing’s syndrome Primary Bilateral Macronodular Adrenal Hyperplasia Cortisol |
| url | https://doi.org/10.1186/s13023-025-03554-1 |
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