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A novel missense mutation in the folliculin gene associated with the renal tumor-only phenotype of Birt-Hogg-Dubé syndrome

      Highlights

      • We report the case of a patient with Birt-Hogg-Dubé syndrome showing the renal tumor-only phenotype.
      • Targeted sequencing of FLCN revealed a novel germline missense mutation (c.602A>C, p.Gln201Pro).
      • Protein analyses revealed that the FLCN missense mutation is pathogenic.
      • Whole-genome sequencing of one of the renal tumors identified another frameshift mutation in FLCN, suggesting a “second hit” mutation for tumorigenesis.
      • Our literature review suggested the relationship between missense mutations and the renal tumor-only phenotype.

      Abstract

      Birt-Hogg-Dubé syndrome is an autosomal dominant disease caused by germline mutations in the folliculin gene (FLCN), characterized by skin fibrofolliculomas, pulmonary cysts, and multiple renal tumors. We report the case of a 51-year-old woman with multiple bilateral renal tumors resected by bilateral open partial nephrectomy. Following pathological diagnosis of hybrid oncocytic/chromophobe tumors, targeted next-generation sequencing of FLCN of the patient's blood revealed a novel missense mutation (c.602A>C, p.Gln201Pro) in exon 6. Sanger sequencing revealed that this mutation was heterozygous. In silico prediction programs consistently indicated the mutation as pathogenic. Western blot analysis and immunohistochemistry revealed suppressed FLCN expression and the upregulation of glycoprotein nonmetastatic B, a downstream target negatively regulated by FLCN, in the tumor tissue, suggesting that the mutation resulted in reduction of functional FLCN expression. Whole-genome sequencing of one of the tumors identified another frameshift mutation in exon 4, suggesting a “second hit” leading to tumorigenesis. We recommend that gene sequencing should be considered in patients with multiple renal tumors to identify their genetic predisposition to renal tumors.

      Keywords

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