KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
Genet Med
; 24(2): 374-383, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34906447
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Prevencao_e_fatores_de_risco
/
Alimentacao
/
Hereditariedade
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Cushing
Tipo de estudo:
Diagnostic_studies
/
Etiology_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Genet Med
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
França