Kidney Week

Abstract: FR-OR069

Next-Generation Sequence Analysis of Genetically Unsolved Primary Hyperoxaluria (PH) or Dent-Diagnosed Patients Resolved 10% of Cases with 11 Genes Implicated

Session Information

• Genetic Diseases and the Kidneys
  November 08, 2019 | Location: 144, Walter E. Washington Convention Center
  Abstract Time: 06:06 PM - 06:18 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Shah, Ronak Jagdeep, Mayo Clinic, Rochester, Minnesota, United States

Ronak Jagdeep Shah, MBBS



I completed my medical school from the prestigious old institution in India - Grant Government Medical College from the city of Mumbai which is ranked among the top 10 institutes of the country. Realizing my interests in nephrology during my work in India, I wanted to learn about advances in Nephrology and was given an opportunity to do research work with Dr. John Lieske at the Mayo Clinic Division of Nephrology in Minnesota where I completed a year of voluntary research work with multiple papers completed. Currently I started my residency in June, 2019 at the Cleveland Clinic Fairview Hospital with the Department of Internal Medicine and hope to keep advancing towards my goal of a fellowship and ultimately a career in the field of Nephrology with possesses great potential of extraction considering the advances we have been making. I hope to work in the future in collaboration with the ASN to keep advancing towards this goal and will look forward to great opportunities to work together.

• Cogal, Andrea G., Mayo Clinic, Rochester, Minnesota, United States

Andrea G. Cogal,

• Sas, David J., Mayo Clinic, Rochester, Minnesota, United States

David J. Sas,

• Lieske, John C., Mayo Clinic, Rochester, Minnesota, United States

John C. Lieske,

• Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States

Peter C. Harris,

Background

Due to phenotypic overlap between patients with monogenic stone diseases, gene specific analysis of patient groups can result in under diagnosis. Here we employed a targeted next generation sequencing (tNGS) approach to analyze primary hyperoxaluria (PH) or Dent diagnosed patients that were genetically unresolved after analysis of the respective known genes by Sanger analysis.

Methods

A cohort of genetically unresolved patients with a presumptive diagnosis of PH (PHN, n=236) and Dent disease (DN, n=61) were screened employing a 90 gene panel that included known monogenic causes of stone disease and candidates. Variants were assessed considering American College of Medical Genetics and Genomics guidelines. Their presence was determined in disease-specific databases, Human Gene Mutation Database (HGMD) and ClinVar, and the frequency in normal populations, GnomAD, plus using variant assessment tools and by analysis of multisequence alignments. Sanger sequencing was used to confirm changes and test segregation.

Results

Biallelic pathogenic variants were found in 11 different genes and accounted for 30 patients (10.1%). Recurrent genes included ones encoding claudins, CLDN16 [6PHN, 1DN] & CLDN19 [1PHN, 1DN] (familial hypomagnesemia with hypercalciuria and nephrocalcinosis), the cystinuria gene, SLC7A9 [5PHN], CYP24A1 [4PHN], SLC34A3 [1PHN, 2DN] (hypophosphatemic rickets with hypercalciuria), and APRT [2PHN]. The genes ATP6V1B1 [1DN], SLC12A1 [1DN] and SLC34A1 [1DN] account for just one family. Mutations to CLDN16, CLDN19, SLC34A3, and KCNJ1 were found to account for both PH and Dent diagnosed patients. Two additional patients were found to have copy number variants, a 72 gene deletion [1PHN] or 2 duplicated regions [1DN], that may be phenotypically significant.

Conclusion

The phenotype of monogenic stone diseases overlaps greatly. Given the emerging therapies for these disorders, including siRNA approaches for PH, making the correct diagnosis is crucial for enrollment in clinical trials and selecting the correct therapy. It is also essential to identify cohorts of patients with poorly recognized disorders, in order to better understand the natural history, and assemble cohorts for future trials.

Funding

• NIDDK Support