A recent paper by Pichert et al. (2011) screened 4805 patients for genetic imbalance in cancer predisposition genes. The patients had been referred to UK clinics for developmental delay, behavioural abnormalities and birth defects. Array CGH was used to detect copy number variations in 47 cancer predisposition genes, including FLCN.
It was found that 29 of the 4805 patients (0.6%) had genetic imbalance in at least one cancer predisposition gene. These included partial and whole gene deletions, as well as duplications. Of these 29 patients, 23 had no symptoms or family history linking them to the suggested syndrome. Although this may appear surprising, no control group was screened and so the relevance of this finding is unclear.
What is interesting is that four patients, aged between 3 and 27, were identified with copy number variations in FLCN. These included three duplications and one deletion. Of the three duplications, two were de novo, whereas the inheritance of the third duplication could not be determined. None of the patients with duplications had symptoms of BHD syndrome.
The inheritance of the identified FLCN deletion could not be determined. The patient was referred for the developmental disorder Smith-Magenis syndrome. The deletion of a region in chromosome 17, close to the FLCN gene, is responsible for most cases of Smith-Magenis syndrome. Symptoms are thought to arise due to the loss of the RAI1 gene, although loss of other genes may also account for the syndrome. Therefore, the deletion of FLCN in this particular patient is not surprising.
The clinical significance of these FLCN copy number variations has not been determined. As none of the patients displayed symptoms of BHD, the mutations may be non-pathogenic. However, it may be that the patients are too young for the onset of BHD symptoms. Pathogenic deletions (Sempau et al., 2010) and duplications (Benhammou et al., 2011) have previously been reported in the FLCN gene, and they have been discussed in previous blog posts (here and here).
Follow-up analysis of the patients identified in this study will help to determine the clinical relevance of these mutations. In the meantime, it is interesting to note the frequency of FLCN mutations in this study compared with genes such as VHL, that are associated with more common diseases. No VHL mutations were identified, perhaps due to the more obvious symptoms of the disease and therefore exclusion of these patients from the study. The difficulty in observing BHD symptoms may mean that FLCN mutations are more common than previously thought.
- Pichert G, Mohammed SN, Ahn JW, Ogilvie CM, Izatt L. Unexpected findings in cancer predisposition genes detected by array comparative genomic hybridisation: what are the issues? J Med Genet. 2011 Mar 23. [Epub ahead of print] PMID:21429933
- Sempau L, Ruiz I, González-Morán A, Susanna X, Hansen TV. [New mutation in the Birt Hogg Dube gene]. [Article in Spanish] Actas Dermosifiliogr. 2010 Sep;101(7):637-40. PMID:20858390
- Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, Wu X, Korolevich S, Nathanson KL, Stolle CA, Linehan WM. Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes Chromosomes Cancer. 2011 Jun;50(6):466-77. PMID:21412933
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.