| Title: | A genome-first approach to characterize DICER1 pathogenic variant prevalence, penetrance and cancer, thyroid, and other phenotypes in 2 population-scale cohorts |
| Journal: | Genetics in Medicine Open |
| Published: | 11 Apr 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39070603/ |
| DOI: | https://doi.org/10.1016/j.gimo.2024.101846 |
| Citations: | 1 (1 in last 2 years) as of 8 Aug 2024 |
Publication 9987
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Abstract
Purpose: Population-scale, exome-sequenced cohorts with linked electronic health records (EHR) permit genome-first exploration of phenotype. Phenotype and cancer risk are well-characterized in children with a pathogenic DICER1 (HGNC ID:17098) variant. Here, the prevalence, penetrance and phenotype of pathogenic germline DICER1 variants in adults was investigated in two population-scale cohorts.</p>
Methods: Variant pathogenicity was classified using published DICER1 ClinGen criteria in the UK Biobank (469,787 exomes; unrelated: 437,663) and Geisinger (170,503 exomes; unrelated: 109,789) cohorts. In the UK Biobank cohort, cancer diagnoses in the EHR, cancer and death registry were queried. For the Geisinger cohort, the Geisinger Cancer Registry and EHR were queried.</p>
Results: In the UK Biobank, there were 46 unique pathogenic DICER1 variants in 57 individuals (1:8,242;95%CI:1:6,362-1:10,677). In Geisinger, there were 16 unique pathogenic DICER1 variants (including one microdeletion) in 21 individuals (1:8,119;95%CI:1:5,310-1:12,412). Cohorts were well-powered to find larger effect sizes for common cancers. Cancers were not significantly enriched in DICER1 heterozygotes; however, there was a ~4-fold increased risk for thyroid disease in both cohorts. There were multiple ICD10 codes enriched >2-fold in both cohorts.</p>
Conclusion: Estimates of pathogenic germline DICER1 prevalence, thyroid disease penetrance and cancer phenotype from genomically ascertained adults are determined in two large cohorts.</p>
11 Authors
- Jung Kim
- Jeremy Haley
- Jessica N Hatton
- Uyenlinh L Mirshahi
- H Shanker Rao
- Mark F Ramos
- Diane Smelser
- Gretchen Urban
- Kris Ann P Schultz
- David J Carey
- Douglas R Stewart
1 Application
| Application ID | Title |
|---|---|
| 54389 | Frequency, phenotypic spectrum, and penetrance of pathogenic variation in cancer susceptibility genes in the general population |
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