Genetic drivers of Cushing 's disease: Frequency and associated phenotypes

Purpose: Cushing's disease (CD) is often explained by a single somatic sequence change. Germline defects, however, often go unrecognized. We aimed to determine the frequency and associated phenotypes of genetic drivers of CD in a large cohort. Methods: We studied 245 unrelated patients with CD (139 female, 56.7%), including 230 (93.9%) pediatric and 15 (6.1%) adult patients. Germline exome sequencing was performed in 184 patients; tumor exome sequencing was also done in 27 of them. Atotal of 43 germline samples and 92 tumor samples underwent Sanger sequencing of specific genes. Rare variants of uncertain significance, likely pathogenic (LP), or pathogenic variants in CD-associated genes, were identified. Results: Germline variants (13 variants of uncertain significance, 8 LP, and 11 pathogenic) were found in 8 of 19 patients (42.1%) with positive family history and in 23 of 226 sporadic patients (10.2%). Somatic variants (1 LP and 7 pathogenic) were found in 20 of 119 tested individuals (16.8%); one of them had a coexistent germline defect. Altogether, variants of interest were identified at the germline level in 12.2% of patients, at the somatic level in 7.8%, and coexisting germline and somatic variants in 0.4%, accounting for one-fifth of the cohort. Conclusion: We report an estimate of the contribution of multiple germline and somatic genetic defects underlying CD in a single cohort. (c) 2022 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.

Automated summary

This study aimed to determine the frequency and associated phenotypes of genetic drivers of Cushing's disease (CD). The study found that about 12.2% of patients had variants of interest at the germline level, 7.8% had variants at the somatic level, and 0.4% had coexisting germline and somatic variants.