Experience in Molecular Genetic Diagnostics of Birt–Hogg–Dubé Syndrome: Characteristics of Identified Mutations and Evolution of the Methodological Approach

Birt–Hogg–Dubé syndrome (BHDS) is a hereditary cancer syndrome caused by pathogenic variants in the FLCN gene. BHDS is characterized by clinical heterogeneity and similarities with other non-hereditary diseases, which can complicate diagnosis. The aim of our study was to analyze FLCN variants in Russian patients and select the optimal diagnostic approach. We studied 121 unrelated patients suspected for BHDS and 29 of their relatives. Germline variants were analyzed using Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Variant annotation was performed according to the ACMG and AMP recommendations. Pathogenic and likely pathogenic (P/LP) FLCN variants were identified in 20.7% of patients, including six new variants. The distribution of FLCN variants in our cohort was consistent with data obtained from other authors. The mean age of patients with P/LP variants was higher than of those without: 46.91 versus 33.8 years (p < 0.05), suggesting the necessity to apply diagnostic criteria in young patients more carefully. The most common clinical manifestation of BHDS was pulmonary cysts/pneumothorax, while the most informative were alterations involving at least two of three organ systems, which was present in all patients with the P/LP variants, but only in 54% without them (p = 0.001). BHDS diagnostics involves sequencing exons 4–14 of the FLCN gene in patients with proposed clinical criteria. If the result is negative, extensive FLCN deletions are excluded using MLPA, and, in the absence of CNV, WGS is performed.