A genome-first approach to characterize DICER1 pathogenic variant prevalence, penetrance and cancer, thyroid, and other phenotypes in 2 population-scale cohorts.

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 (HGNC ID:17098) variant. Here, the prevalence, penetrance and phenotype of pathogenic germline variants in adults was investigated in two population-scale cohorts.

Methods: Variant pathogenicity was classified using published 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 variants in 57 individuals (1:8,242;95%CI:1:6,362-1:10,677). In Geisinger, there were 16 unique pathogenic 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 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 prevalence, thyroid disease penetrance and cancer phenotype from genomically ascertained adults are determined in two large cohorts.