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. 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. 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. Conclusion: Estimates of pathogenic germline DICER1 prevalence, thyroid disease penetrance and cancer phenotype from genomically ascertained adults are determined in two large cohorts.
