There have been occasional reports of patients presenting with clinical BHD symptoms but in whom no small FLCN mutation can be identified using standard sequencing techniques. However, more recently larger deletions within FLCN have been identified in a some of these patients.
A new report from Ding et al., (2015) has identified three such large deletions in the FLCN genes of nine unrelated Chinese families; two families show the same deletion within exons 1-3, five share a deletion in exons 9-14, and a further two have a deletion within exon 14. The group used Multiplex Ligation-dependent Probe Amplification (MLPA) assays and breakpoint analysis to map deletions in families with a history of primary spontaneous pneumothorax and pulmonary cysts but no previously detectable FLCN mutations (n=12). None of the deletions detected in these families were found in unrelated controls. Interestingly all three deletions showed evidence of haplotype inheritance – the larger exon 9-14 deletion was estimated to have occurred 16 generations (approximately 400 years) ago and could represent a founder mutation.