Using whole-exome sequencing to investigate the genetic bases of lysosomal storage diseases of unknown etiology

5 years ago

Using whole-exome sequencing to investigate the genetic bases of lysosomal storage diseases of unknown etiology

David E. Sleat, Yeting Zhang, Nan Wang, Timothy Lin, Peter Lobel, Edward H. Schuchman, Kimiyo Raymond, Chang-Gong Liu, Xiuping Liu, Jinchuan Xing, Robert Donnelly, Erika Gedvilaite, Jui Wan Loh, Dibyendu Kumar

Lysosomes are membrane-bound, acidic eukaryotic cellular organelles that play important roles in the degradation of macromolecules. Mutations that cause the loss of lysosomal protein function can lead to a group of disorders categorized as the lysosomal storage diseases (LSDs). Suspicion of LSD is frequently based on clinical and pathologic findings, but in some cases, the underlying genetic and biochemical defects remain unknown. Here, we performed whole-exome sequencing (WES) on 14 suspected LSD cases to evaluate the feasibility of using WES for identifying causal mutations. By examining 2,157 candidate genes potentially associated with lysosomal function, we identified eight variants in five genes as candidate disease-causing variants in four individuals. These included both known and novel mutations. Variants were corroborated by targeted sequencing and, when possible, functional assays. In addition, we identified nonsense mutations in two individuals in genes that are not known to have lysosomal function. However, mutations in these genes could have resulted in phenotypes that were diagnosed as LSDs. This study demonstrates that WES can be used to identify causal mutations in suspected LSD cases. We also demonstrate cases where a confounding clinical phenotype may potentially reflect more than one lysosomal protein defect. Lysosomes play important roles in the degradation of macromolecules, and the loss of lysosomal protein function leads to the lysosomal storage diseases (LSDs). We performed whole exome sequencing on 14 suspected LSD cases and identified candidate disease-causing variants in both known and novel genes. We also demonstrate cases where a confounding clinical phenotype may potentially reflect more than one lysosomal protein defect.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/humu.23291