Birt-Hogg-Dubé syndrome, prevalence of identified cases according to clinical indication in a cohort of 1,084 patients with genetic analysis.

FLCN

Germline pathogenic FLCN variants, including two mosaic variants

This study analysed clinical and molecular data from 1,084 consecutive probands referred for suspected Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant disorder caused by FLCN. A pathogenic FLCN variant was found in 29% of them, with the highest yield for isolated fibrofolliculomas (55.8%; 95% CI 44.7-66.5%), versus 4.8% for isolated pulmonary cysts and 0.6% for isolated renal cancer. In multivariable analysis, fibrofolliculomas (OR = 12.9) and pneumothorax (OR = 5.8) were the strongest predictors, and a family history of BHD-related symptoms increased the likelihood of detection. Among 244 relatives carrying the familial variant, only 60% of those aged 50-60 years had developed BHD-related symptoms, and two patients with a mosaic variant were identified.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

These yields by clinical presentation directly help prioritise testing indications, first and foremost for fibrofolliculomas or pneumothorax. The low yield for isolated renal cancer (0.6%) calls for calibrating the information given to the patient before testing. Incomplete penetrance in relatives aged 50-60 and the finding of mosaic cases support cascade testing and attention to allele fraction on exome/genome.

Analysis by Dr Thibaut Benquey