Frequency of FLCN Loss of Function Variants and Birt-Hogg-Dube-Associated Phenotypes in a Healthcare System Population

PurposeCurrent penetrance estimates of Birt-Hogg-Dube (BHD)-associated cutaneous, pulmonary, and renal manifestations are based on clinically ascertained families. In a healthcare system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) variants in the FLCN gene, which cause BHD, and the penetrance of BHD-related phenotypes. MethodsExomes from 135,990 patient-participants in Geisingers MyCode(R) cohort were assessed for P/LP FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between FLCN P/LP variants and BHD-related phenotypes were assessed by Firths logistic regression. ResultsP/LP FLCN variants were identified in 35 (1 in 3,234) individuals, 68.6% of whom had BHD-related phenotype(s) including: cystic lung disease (65.7%); pneumothoraces (17.1%); cutaneous manifestations (8.6%); and renal cancer (2.9%). Only four (11.4%) were clinically diagnosed with BHD. ConclusionIn this healthcare population, the frequency of P/LP FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes in the EHR, a minority were clinically diagnosed with BHD, likely because cutaneous manifestations, pneumothoraces, and renal cancer were observed at lower frequencies than clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.