KDM1A inactivation causes hereditary food-dependent Cushing syndrome

Anna Vaczlavik; Lucas Bouys; Florian Violon; Gaetan Giannone; Anne Jouinot; Roberta Armignacco; Isadora P Cavalcante; Annabel Berthon; Eric Letouzé; Patricia Vaduva; Maxime Barat; Fidéline Bonnet; Karine Perlemoine; Christopher Ribes; Mathilde Sibony; Marie-Odile North; Stéphanie Espiard; Philippe Emy; Magalie Haissaguerre; Igor Tauveron; Laurence Guignat; Lionel Groussin; Bertrand Dousset; Martin Reincke; Maria C Fragoso; Constantine A Stratakis; Eric Pasmant; Rossella Libé; Guillaume Assié; Bruno Ragazzon; Jérôme Bertherat

doi:10.1016/j.gim.2021.09.018

KDM1A inactivation causes hereditary food-dependent Cushing syndrome

Genet Med. 2022 Feb;24(2):374-383. doi: 10.1016/j.gim.2021.09.018. Epub 2021 Nov 30.

Authors

Anna Vaczlavik¹, Lucas Bouys², Florian Violon³, Gaetan Giannone², Anne Jouinot⁴, Roberta Armignacco², Isadora P Cavalcante², Annabel Berthon², Eric Letouzé⁵, Patricia Vaduva⁶, Maxime Barat⁷, Fidéline Bonnet⁸, Karine Perlemoine², Christopher Ribes², Mathilde Sibony³, Marie-Odile North⁹, Stéphanie Espiard¹⁰, Philippe Emy¹¹, Magalie Haissaguerre¹², Igor Tauveron¹³, Laurence Guignat¹⁴, Lionel Groussin¹, Bertrand Dousset¹⁵, Martin Reincke¹⁶, Maria C Fragoso¹⁷, Constantine A Stratakis¹⁸, Eric Pasmant¹⁹, Rossella Libé¹, Guillaume Assié¹, Bruno Ragazzon², Jérôme Bertherat²⁰

Affiliations

¹ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
² Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France.
³ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Pathology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
⁴ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France; Institut Curie, INSERM U900, MINES ParisTech, PSL-Research University, CBIO-Centre for Computational Biology, Paris, France.
⁵ Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris France.
⁶ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France.
⁷ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Radiology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
⁸ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Unit of Hormonology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
⁹ Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
¹⁰ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Lille, France.
¹¹ Department of Endocrinology, CHR Orleans, Orléans, France.
¹² Department of Endocrinology, University of Bordeaux and CHU Bordeaux, Bordeaux, France.
¹³ Department of Endocrinology, CHU Clermont Ferrand, Clermont-Ferrand, France.
¹⁴ Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
¹⁵ Department of Digestive and Endocrine Surgery, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
¹⁶ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
¹⁷ Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil.
¹⁸ Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD.
¹⁹ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
²⁰ Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. Electronic address: jerome.bertherat@aphp.fr.

PMID: 34906447
DOI: 10.1016/j.gim.2021.09.018

Abstract

Purpose: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS.

Methods: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing).

Results: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10^-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS.

Conclusion: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.

Keywords: ARMC5; Adrenocortical tumors; Cushing syndrome; GIPR; KDM1A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Armadillo Domain Proteins / genetics
Cushing Syndrome* / diagnosis
Cushing Syndrome* / genetics
Cushing Syndrome* / surgery
Histone Demethylases / genetics
Humans
Hyperplasia
Phenotype

Substances

Armadillo Domain Proteins
Histone Demethylases
KDM1A protein, human