Abstract: TH-PO716
A Custom Next Generation Sequencing (NGS) Panel for Kidney Stone Disease Resolves Diagnosis in Mutation Negative Patients Clinically Diagnosed with Dent Disease
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - I
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1002 Genetic Diseases of the Kidney: Non-Cystic
Authors
- Cogal, Andrea G., Mayo Clinic , Rochester, Minnesota, United States
- Senum, Sarah R., Mayo Clinic , Rochester, Minnesota, United States
- Cornec-Le Gall, Emilie, Centre Hospitalier Universitaire de Brest, BREST, France
- Seide, Barbara M., Mayo Clinic , Rochester, Minnesota, United States
- Banks, Carly, Mayo Clinic , Rochester, Minnesota, United States
- Olson, Julie B., Mayo Clinic , Rochester, Minnesota, United States
- Greenwood, Tammy M., Mayo Clinic , Rochester, Minnesota, United States
- Sas, David J., Mayo Clinic , Rochester, Minnesota, United States
- Milliner, Dawn S., Mayo Clinic , Rochester, Minnesota, United States
- Beara Lasic, Lada, NYU Medical Center, Pelham, New York, United States
- Lieske, John C., Mayo Clinic , Rochester, Minnesota, United States
- Harris, Peter C., Mayo Clinic , Rochester, Minnesota, United States
Group or Team Name
- Rare Kidney Stone Consortium (RKSC)
Background
Dent disease is an X-linked disorder characterized by low molecular weight proteinuria, nephrolithiasis/nephrocalcinosis and CKD. We previously performed molecular screening of suspected Dent patients by Sanger sequencing of the known genes: CLCN5 and OCRL. The majority of cases were genetically resolved, but there remained a cohort with no mutations detected (NMD), which we analyze here employing a NGS panel.
Methods
A NGS panel consisting of 90 known and candidate genes related to urinary stone risk was developed and 61 NMD suspected Dent families screened. The phenotype of resolved patients was compared to the implicated gene.
Results
Likely pathogenic mutations consistent, or in one case divergent, with the presenting phenotype were detected in 5 (8%) of the 61 NMD families (Table). Two cases with SLC34A3 mutations were detected, one with a missense, an inframe deletion and a splicing mutation and a second homozygous for a novel frameshifting duplication. SLC12A1 biallelic missense mutations were found in a patient with a typical Bartter phenotype. A patient with a KCNJ1 frameshifting duplication and missense mutation had nephrocalcinosis, proteinuria, and CKD, but lacked the typical electrolyte abnormalities of Barrter. One subject was homozygous for a previously described CLDN16 missense mutation. An additional patient was found to have two large chromosomal duplications, confirmed by MLPA and microarray analysis, which we have categorized as possibly pathogenic. Three additional patients with weaker biallelic variants in candidate genes are being further assessed.
Conclusion
This analysis demonstrates the utility of a panel-based NGS approach in unresolved patients with suspected monogenic causes of nephrocalcinosis or urinary stone disease and is valuable since the phenotypes of these disorders can demonstrate significant divergence and overlap.
| Gene | Age of Presentation | Sex | Affected Family Members | Nephrocalcinosis | Hypercalciuria | Proteinuria (>1g) | LMWP | CKD |
| SLC34A3 | 17 | F | Y | Y | Y | Y | Y | Y |
| SLC34A3 | 8 | M | Y | Y | Y | N | U | Y |
| SLC12A1 | 3 | M | N | Y | Y | Y | Y | N |
| KCNJ1 | 55 | M | Y | Y | Y | Y | Y | Y |
| CLDN16 | 2 | M | U | Y | Y | Y | U | Y |
Funding
- NIDDK Support