I attended the British Renal Society/Renal Association’s annual conference this week in Manchester, UK. It was well attended and addressed current clinical practice and basic research into a range renal disorders. Unfortunately, there were no specific talks on BHD Syndrome but it was really interesting seeing how current renal genetics services were being integrated with established clinical pathways.
One specific talk on the subject of polycystic kidney disease highlighted the effect that certain genetic mutations can have on the phenotypic presentation of a disorder and I’d like to share that in the context of BHD.
We understand that BHD is a monogenic disorder, that is to say it’s caused by inactivation of a single gene, FLCN, which inevitably results in abnormal protein function within critical cell signalling pathways that underpin normal growth and development.
A range of causative pathogenic mutations have been identified (and even catalogued by Wei et al and Lim et al*). This has also lead to the development of a molecular diagnostic assay used to provide a positive diagnosis of BHD Syndrome.
It is essential to identify and characterise all mutations since some of these may act as pathogenic missense variants or hypomorphic alleles. Such mutations are not as immediately pathogenic as deleterious nonsense mutations but may be able to alter protein function if they arise within a highly conserved domain of the protein. They can account for milder phenotypes or even a disparity in the presentation of symptoms and significantly, rare missense variants can also be inherited and so give rise to familial disease.
*FLCN mutation databases by Wei et al: www.skingenedatabase.com; and Lim et al: www.lovd.nl/flcn