Genetic Variations That Increase the Risk for Calcium Kidney Stones: a Family-based Study

Many things, like not drinking enough fluids, contribute to making kidney stones and there is also a genetic tendency. We looked into this in 1998-2000 in 14 families with several stone-formers. In four of these the risk for stones was passed down through one line of the family. We have now had a close look at the DNA of 47 members of these four families using a very sensitive technique called exome sequencing. We wanted to see if these individuals had inherited any rare changes (variations) in their DNA which would add to their risk of making stones. We found 11 variations which might be important. Surprisingly, these were not in genes which have been regarded as the main causes of stones. Most of them are unfamiliar to clinicians and scientists world-wide. Experts on the genes gave us helpful advice about the likely significance of the variations. Researchers in Paris, Lille and the UK (Oxford, Cambridge and Sheffield) did analyses to help to decide this. An exciting finding was that one of the variants, not previously identified in stone formers, had just been found in a large Italian family with stones. This small study has shown that: variations in a wide range of genes may contribute to stone formation; these occur in genes that we have not come across before; further laboratory studies are essential to investigate potentially important variants; sharing findings between laboratories doing similar studies world-wide is crucial.