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

doi:10.1016/j.gim.2022.08.021

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	2516-2525
Number of pages	10
Journal	Genetics in Medicine
Volume	24
Issue number	12
DOIs	https://doi.org/10.1016/j.gim.2022.08.021
State	Published - 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

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Intramural

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10.1016/j.gim.2022.08.021

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title = "Genetic drivers of Cushing's disease: Frequency and associated phenotypes",

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.",

keywords = "Corticotropinoma, Cushing's disease, Exome sequencing, Germline variant, Pituitary tumor",

author = "Hern{\'a}ndez-Ram{\'i}rez, {Laura C.} and Nathan Pankratz and John Lane and Faucz, {Fabio R.} and Prashant Chittiboina and Kay, {Denise M.} and Zachary Beethem and Mills, {James L.} and Stratakis, {Constantine A.}",

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: {\textcopyright} 2022 American College of Medical Genetics and Genomics",

year = "2022",

month = dec,

doi = "10.1016/j.gim.2022.08.021",

language = "English (US)",

volume = "24",

pages = "2516--2525",

journal = "Genetics in Medicine",

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TY - JOUR

T1 - Genetic drivers of Cushing's disease

T2 - Frequency and associated phenotypes

AU - Hernández-Ramírez, Laura C.

AU - Pankratz, Nathan

AU - Lane, John

AU - Faucz, Fabio R.

AU - Chittiboina, Prashant

AU - Kay, Denise M.

AU - Beethem, Zachary

AU - Mills, James L.

AU - Stratakis, Constantine A.

N1 - 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

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - Corticotropinoma

KW - Cushing's disease

KW - Exome sequencing

KW - Germline variant

KW - Pituitary tumor

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SN - 1098-3600

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JO - Genetics in Medicine

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

Abstract

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Keywords

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