Advances in whole-exome sequencing have allowed unprecedented success in the identification of mutations that result in Mendelian diseases. In collaboration with colleagues at the OUHSC, Dr. Gaffney has developed a genomic sequencing pipeline to identify causal mutations and diagnose families with Mendelian disorders. To date, Dr. Gaffney and his colleagues have identified constitutive gain-of-function mutations in STIM1 and ORAI1 that explain Stormorken syndrome (Nesin, et al. Proc Natl Acad Sci USA 2014), four recessive mutations in the KEOPS complex subunits OSGEP, TP53RK, TPRKB, and LAGE3 that are causative to Galloway-Mowat Syndrome (Braun, et al. Nat Genet 2017), bi-allelic pathogenic SPTBN4 mutations (three homozygous; two compound heterozygous) that define a class of spectrinopathies (Wang, et al. Am J Hum Genet 2018), and novel biallelic variants in MBTPS1 that cause ER stress and lysosomal dysregulation in chondrocytes resulting in a rare pediatric skeletal disease (Kondo, et al. JCI Insight 2018).
Scientific advances, even those aimed at identifying the genetic mutation responsible for a rare genetic disease, most often provide insights into the origin of a disease and, possibly, new targets for future therapeutic discoveries. Rarely do scientific discoveries provide information that can be used to immediately save an individual’s life. However, in 2015, Dr. Gaffney and his long-time colleague and geneticist, Dr. Klaas Wierenga, discovered a genetic mutation in the DNA sequence of a 13-year-old boy that ultimately saved his life. More information about this amazing story can be found here.