Advances in genetic technologies over the last decade have allowed discovery of over 50 genetic variants that contribute to the risk of type 1 diabetes (T1D). Despite this success, these variants still do not account for the total genetic risk of developing this disease. To account for this “missing heritability”, the “Common Disease-Rare Variant” hypothesis has been proposed. This postulates that diseases may be caused by rare DNA variants which have a higher individual impact on disease risk than the known common variants. However, such rare variants have not yet been discovered because different people with the same common disease have rare variants in different genes.
We investigated an unusual family which has members over five generations that have developed T1D. DNA samples were genotyped from affected and unaffected family members and selected samples from family members from three different generations also had whole-exome sequencing. Linkage studies were inconclusive (due to lack of power) but shared haplotype analyses indicated only one region was shared by all six affected family members.
This region contained six novel genetic variants. One of these is in the gene encoding the enzyme S-adenosyl-homocysteine hydrolase. Characterization of the effects of this mutation will be presented.