生殖系
桑格测序
外显子组测序
种系突变
遗传学
体细胞
生物
外显子组
队列
表型
疾病
医学
基因
突变
内科学
作者
Laura C Hernández-Ramírez,Nathan Pankratz,John Lane,Fabio R. Faucz,Prashant Chittiboina,Denise M. Kay,Zachary T. Beethem,James L. Mills,Constantine A. Stratakis
标识
DOI:10.1016/j.gim.2022.08.021
摘要
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.
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