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Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease

Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease


Title: Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease
Author: Investigators of the Rare Kidney Stone Consortium
Date: 2021-11
Language: English
Scope: 23
Department: Faculty of Medicine
Women's and Childrens's Services
Office of Division of Clinical Services I
Series: Kidney International Reports; 6(11)
ISSN: 2468-0249
DOI: https://doi.org/10.1016/j.ekir.2021.08.033
Subject: Nýrnasteinar; Sameindaerfðafræði; Dent disease; kidney stones; molecular genetics; monogenic; primary hyperoxaluria; Nephrology
URI: https://hdl.handle.net/20.500.11815/3042

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Citation:

Investigators of the Rare Kidney Stone Consortium 2021 , ' Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease ' , Kidney International Reports , vol. 6 , no. 11 , pp. 2862-2884 . https://doi.org/10.1016/j.ekir.2021.08.033

Abstract:

Introduction: Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. Methods: Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. Results: Screening by tNGS revealed pathogenic variants in 14 known monogenic USD genes, accounting for 45 families (13.1%), 27 biallelic and 18 monoallelic, including 1 family with a copy number variant (CNV). Recurrent genes included the following: SLC34A3 (n = 13), CLDN16 (n = 8), CYP24A1 (n = 4), SLC34A1 (n = 3), SLC4A1 (n = 3), APRT (n = 2), CLDN19 (n = 2), HNF4A1 (n = 2), and KCNJ1 (n = 2), whereas ATP6V1B1, CASR, and SLC12A1 and missed CNVs in the PH genes AGXT and GRHPR accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. Conclusion: Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials.

Description:

Publisher Copyright: © 2021 International Society of Nephrology Funding text 1 Funding for this project was provided by U54-DK083908 from the National Institute of Diabetes and Digestive and Kidney Diseases , National Center for Advancing Translational Sciences , R21TR003174 from the National Center for Advancing Translational Sciences , and the Oxalosis & Hyperoxaluria Foundation (OHF). JA was supported by the Mayo Clinic Kidney Diseases Training grant ( T32 DK07013 ). We thank all of the patients and families who have participated in the RKSC PH and DD registries as well as the many physicians who collected the detailed clinical records (see below). Katharina Hopp and Emilie Cornec Le Gall helped with initially establishing the NGS. Furthermore, we thank the study coordinators who collected clinical data and biological samples. We also thank the Mayo Biospecimens Accessioning and Processing, Genome Analysis, and Bioinformatics Cores for their help with the study. Funding text 2 Funding for this project was provided by U54-DK083908 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, R21TR003174 from the National Center for Advancing Translational Sciences, and the Oxalosis & Hyperoxaluria Foundation (OHF). JA was supported by the Mayo Clinic Kidney Diseases Training grant (T32 DK07013). We thank all of the patients and families who have participated in the RKSC PH and DD registries as well as the many physicians who collected the detailed clinical records (see below). Katharina Hopp and Emilie Cornec Le Gall helped with initially establishing the NGS. Furthermore, we thank the study coordinators who collected clinical data and biological samples. We also thank the Mayo Biospecimens Accessioning and Processing, Genome Analysis, and Bioinformatics Cores for their help with the study. We thank the following medical professionals for referring patients who were resolved during the study: ... Funding text 3 DSG: research funded by Travere, Dicerna; consultant, Alnylam; equity in Dr. Arnie’s, Inc. PCH: research funded by National Institutes of Health (NIH). JCL: research funded from NIH and The Oxalosis and Hyperoxaluria Foundation, is on the scientific advisory board of Alnylam and Dicerna and member of the data safety monitoring board of Alnylam. DSM: research funded from NIDDK and The Oxalosis and Hyperoxaluria Foundation. DJS: grant funding from Alnylam; funding from Alnylam for directorship of the CME program. All the other authors declared no competing interests.

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