Using whole‐exome sequencing to investigate the genetic bases of lysosomal storage diseases of unknown etiology |
| |
| Authors: | Erika Gedvilaite Jui Wan Loh Timothy Lin Xiuping Liu Chang‐Gong Liu Dibyendu Kumar Robert Donnelly Kimiyo Raymond Edward H. Schuchman David E. Sleat Peter Lobel Jinchuan Xing |
| |
| Affiliation: | 1. Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey;2. Sequencing and ncRNA Program, Department of Experimental Therapeutics, The University of Texas‐MD Anderson Cancer Center, Houston, Texas;3. Waksman Institute of Microbiology, Rutgers, the State University of New Jersey, Piscataway, New Jersey;4. Molecular Resource Facility at Rutgers, New Jersey Medical School, Newark, New Jersey;5. Department of Laboratory Medicine and Pathology, Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota;6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York;7. Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, New Jersey;8. Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, New Jersey;9. Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, New Jersey |
| |
| Abstract: | 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. |
| |
| Keywords: | disease‐causing variants identification lysosomal storage diseases metabolic disorders whole‐exome sequencing |
|
|
