KDM1A inactivation causes hereditary food-dependent Cushing syndrome
Anna Vaczlavik
(1, 2)
,
Lucas Bouys
(1)
,
Florian Violon
(1, 2)
,
Gaetan Giannone
(1)
,
Anne Jouinot
(1, 2, 3)
,
Roberta Armignacco
(1)
,
Isadora P Cavalcante
(1)
,
Annabel Berthon
(1)
,
Eric Letouze
(4)
,
Patricia Vaduva
(1, 5)
,
Maxime Barat
(1, 2)
,
Fideline Bonnet
(1, 2)
,
Karine Perlemoine
(1)
,
Christopher Ribes
(1)
,
Mathilde Sibony
(1, 2)
,
Marie-Odile North
(2)
,
Stephanie Espiard
(1, 6)
,
Philippe Emy
(7)
,
Magalie Haissaguerre
(8, 9)
,
Igor Tauveron
(10)
,
Laurence Guignat
(2)
,
Lionel Groussin
(2, 1)
,
Bertrand Dousset
(2)
,
Martin Reincke
(2)
,
Maria C Fragoso
(11)
,
Constantine A Stratakis
(12)
,
Eric Pasmant
(2, 1)
,
Rossella Libe
(2, 1)
,
Guillaume Assie
(2, 1)
,
Bruno Ragazzon
(1)
,
Jerome Bertherat
(2, 1)
1
IC UM3 (UMR 8104 / U1016) -
Institut Cochin
2 Hôpital Cochin [AP-HP]
3 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
4 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
5 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
6 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
7 CHRO - Centre Hospitalier Régional d'Orléans
8 UB - Université de Bordeaux
9 CHU Bordeaux
10 CHU Clermont-Ferrand
11 USP - Universidade de São Paulo = University of São Paulo
12 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
2 Hôpital Cochin [AP-HP]
3 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
4 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
5 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
6 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
7 CHRO - Centre Hospitalier Régional d'Orléans
8 UB - Université de Bordeaux
9 CHU Bordeaux
10 CHU Clermont-Ferrand
11 USP - Universidade de São Paulo = University of São Paulo
12 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
Anne Jouinot
- Fonction : Auteur
- PersonId : 753239
- IdHAL : anne-jouinot
- ORCID : 0000-0002-7922-2065
Bertrand Dousset
- Fonction : Auteur
- PersonId : 776416
- ORCID : 0000-0003-2526-7345
- IdRef : 058941568
Martin Reincke
- Fonction : Auteur
- PersonId : 758957
- ORCID : 0000-0002-9817-9875
Eric Pasmant
- Fonction : Auteur
- PersonId : 740344
- IdHAL : eric-pasmant
- ORCID : 0000-0002-1881-8762
- IdRef : 112215890
Résumé
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.