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

  • Laura C. Hernández-Ramírez
    Affiliations
    Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD

    Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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  • Nathan Pankratz
    Affiliations
    Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN
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  • John Lane
    Affiliations
    Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN
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  • Fabio R. Faucz
    Affiliations
    Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD
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  • Prashant Chittiboina
    Affiliations
    Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD
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  • Denise M. Kay
    Affiliations
    Newborn Screening Program, Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY
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  • Zachary Beethem
    Affiliations
    Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN
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  • James L. Mills
    Affiliations
    Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD
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  • Constantine A. Stratakis
    Correspondence
    Correspondence and requests for materials should be addressed to Constantine A. Stratakis, Human Genetics & Precision Medicine, IMBB, FORTH, Foundation for Research & Technology – Hellas, Nikolaou Plastira 100, Heraklion, Crete, GR-70013, Greece
    Affiliations
    Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD

    Human Genetics & Precision Medicine, IMBB, FORTH, Heraklion, Crete

    ELPEN Research Institute, Athens, Greece
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Published:September 23, 2022DOI:https://doi.org/10.1016/j.gim.2022.08.021

      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

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