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

Laura C. Hernández-Ramírez, Nathan Pankratz, John Lane, Fabio R. Faucz, Prashant Chittiboina, Denise M. Kay, Zachary Beethem, James L. Mills, Constantine A. Stratakis

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)2516-2525
Number of pages10
JournalGenetics in Medicine
Volume24
Issue number12
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding 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.

Funding 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. 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.

Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics

Keywords

  • Corticotropinoma
  • Cushing's disease
  • Exome sequencing
  • Germline variant
  • Pituitary tumor

Fingerprint

Dive into the research topics of 'Genetic drivers of Cushing's disease: Frequency and associated phenotypes'. Together they form a unique fingerprint.

Cite this