Research Awards Recipients

Lay Summary

Polycystic kidney disease (PKD) comprises a collection of common and rare genetic diseases. With a prevalence of ~1 per 1000 births, autosomal dominant polycystic kidney disease (ADPKD) is the most common cause. Correct diagnosis of ADPKD is important since we now have a drug, Tolvaptan, which can be used to slow kidney failure in ADPKD, but not in other forms of PKD. When there is a family history, ADPKD is typically diagnosed by an ultrasound scan. However, patients without a positive family history, with an atypical kidney imaging patterns, with extreme disease variability in their family, with very mild disease but no PKD1 and PKD2 mutations, or with discordant results of their PKD severity between kidney imaging and kidney function tests, are said to have “atypical PKD”. Identifying the cause of “atypical PKD” in any given patient (i.e. identifying the specific cystic disease gene mutations) typically requires mutation screening of multiple disease genes beyond those involved in ADPKD and is expensive and time consuming. Additionally, some patients with “atypical PKD” may have a condition called “somatic mosaicism” in which PKD was acquired during early embryo development affecting only one of several stem cells which eventually give raise to a mixture of normal and mutated cells that made up the different organs and tissues. As a result, the disease is diluted and presents in an atypical pattern. Currently mutation screening by Sanger sequencing will miss mosaic mutations because their mutation signal is very low. 

Recent advances in Next Generation Sequencing (NGS) has revolutionized novel disease gene discovery and is transforming our approach in molecular diagnostics by providing high-throughput mutation screening of multiple genes at a modest cost. Furthermore, by providing extremely high DNA sequence read depth permitting detection of low mutation signals for a disease gene of interest, NGS is a promising technology for identifying mosaic mutations. Using this new technology, Dr. Pei will identify the genetic causes of ~300 patients with atypical PKD. The identification of cystic disease gene mutations is expected to provide important insights into the causes of atypical PKD. His work will accelerate the development of cost-effective molecular diagnostic testing for this challenging clinical problem.