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KDM1A inactivation causes hereditary food-dependent Cushing syndrome

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

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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