LSD1/KDM1A Inactivation Causes Hereditary Food-Dependent Cushing’s Syndrome

Purpose: To investigate the genetic cause of Food-dependent Cushing’s syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the GIP receptor (GIPR). Germline ARMC5 alterations have been reported in about 25 % of PBMAH index cases but are absent in patients with FDCS. Methods: A multi-omics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNAseq, SNP array, methylome, miRNome, exome sequencing). Results: The integrative analysis revealed three molecular groups with different clinical features: G1, PBMAH due to ARMC5 inactivating variants; G2, with GIPR ectopic expression and FDCS; and G3, with a less severe phenotype. Exome sequencing revealed germline truncating variants of LSD1/KDM1A in the G2 group, constantly associated with a somatic loss of the LSD1/KDM1A wildtype allele on 1p, leading to a loss of LSD1/KDM1A expression both at mRNA and protein levels (p=1.2x10-12 and p<0.01, respectively). Subsequently, LSD1/KDM1A pathogenic variants were identified in 4/4 additional index cases with FDCS. Conclusion: LSD1/KDM1A inactivation explains about 90 % of FDCS PBMAH. Genetic screening for ARMC5 and LSD1/KDM1A can be offered now for the majority of PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.