ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22146830 Houweling et al. 2011 presented the clinical data of 115 FLCN mutation carriers from 35 Birt?Hogg?Dub? (BDH) families. In two of the families with clinical BHD but without a mutation in the coding region of FLNC, a deletion of exon 1 was observed. Exon 1 is the first of three non-coding exons. The exact size and the effects of these deletions remain to be determined.
20413710 Kunogi et al. 2010 studied 36 patients with multiple lung cysts of undetermined causes. Denaturing high performance liquid chromatography and qPCR were applied for mutation screening. An FLCN germline mutation was found in 23 (63.9%) of the 36 patients by DHPLC and direct sequencing (13 unique small nucleotide alterations, which included 11 novel mutations). A large genomic deletion was identified in two of the remaining 13 patients by qPCR (one patient with exon 14 deletion and one patient with a deletion encompassing exons 9 to 14). Mutations including genomic deletions were most frequently identified in the 3'-end of the FLCN gene including exons 12 and 13 (13/25=52.0%).
21412933 Benhammou et al. 2011 identified six intragenic deletions and one intragenic duplication in 47% (7/15) of unrelated BHDS families and characterized 5 of 7 breakpoints. Data from this study confirm that, in addition to frameshift, missense, nonsense and splice-site mutations, BHDS can be caused by intragenic CNVs.

Haploinsufficiency phenotype comments:

Deletion and loss-of-function mutation of FLCN is associated with autosomal dominant Birt?Hogg?Dub? syndrome (BHDS), characterized by predisposition to develop cutaneous manifestations, pulmonary cysts, pneumothorax, and various types of renal tumors. Typical age of onset occurs in the third or fourth decade. Genotype-phenotype associations are not well-established in BHDS. Penetrance is considered to be high. The majority of mutations reported in BHDS are sequence-level alterations. Intragenic, exon-level deletions and duplications have also been reported in BHDS. Reports of focal, whole gene FLCN deletion are lacking. Note that FLCN resides within a segmental duplication-flanked region of 17p11.2 that is recurrently deleted in Smith-Magenis syndrome, however the contribution of FLCN haploinsufficiency in SMS in unknown.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

As yet, focal duplication of FLCN has not been reported in association with clinical phenotypes; therefore the triplosensitivity score is 0. PMID 21429933: Pichert et al., 2011 report three patients with non-focal duplication of FLCN. The smallest duplication was 412 kb, encompassing FLCN and 4 other genes (overlapping NTSM). Intragenic duplications that presumably result in functional inactivation of FLCN have been reported in BHDS (PMIDs 21412933 and 12204536).