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. A total 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.
|Original language||English (US)|
|Number of pages||10|
|Journal||Genetics in Medicine|
|State||Published - Dec 2022|
Bibliographical noteFunding Information:
This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health & Human Development, and the National Institute for Neurological Disorders and Stroke, National Institutes of Health . Clinical trial registration: ClinicalTrials.gov NCT00001595.
This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health & Human Development, and the National Institute for Neurological Disorders and Stroke, National Institutes of Health. Clinical trial registration: ClinicalTrials.gov NCT00001595. Conceptualization: L.C.H.-R. J.L.M. C.A.S.; Data Curation: N.P. J.L. Z.B.; Formal Analysis: L.C.H.-R. D.M.K.; Funding Acquisition: P.C. J.L.M. C.A.S.; Investigation: L.C.H.-R. N.P. J.L. F.R.F. P.C. J.L.M. C.A.S.; Methodology: L.C.H.-R.; Project Administration: J.L.M. C.A.S.; Resources: J.L.M. C.A.S.; Software: N.P. J.L. Z.B.; Supervision: D.M.K. J.L.M. C.A.S.; Validation: L.C.H.-R. F.R.F.; Visualization: L.C.H.-R.; Writing-original draft: L.C.H.-R.; Writing-review and editing: L.C.H.-R, N.P. J.L. F.R.F. P.C. D.M.K. Z.B. J.L.M. C.A.S. Individuals and their parents or guardians provided informed assent or consent and were recruited under protocol 97-CH-0076 (ClinicalTrials.gov: NCT00001595), approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Institutional Review Board.
© 2022 American College of Medical Genetics and Genomics
- Cushing's disease
- Exome sequencing
- Germline variant
- Pituitary tumor
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Intramural