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.
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.
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.
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.
Kidney international reports. 2021 Sep 08*** epublish ***
Andrea G Cogal, Jennifer Arroyo, Ronak Jagdeep Shah, Kalina J Reese, Brenna N Walton, Laura M Reynolds, Gabrielle N Kennedy, Barbara M Seide, Sarah R Senum, Michelle Baum, Stephen B Erickson, Sujatha Jagadeesh, Neveen A Soliman, David S Goldfarb, Lada Beara-Lasic, Vidar O Edvardsson, Runolfur Palsson, Dawn S Milliner, David J Sas, John C Lieske, Peter C Harris, Investigators of the Rare Kidney Stone Consortium
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA., Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA., Children's Hospital, Boston, Massachusetts, USA., Mediscan Systems, Mylapore, Chennai, Tamil Nadu, India., Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt., Nephrology Division, New York University Langone Health and New York University School of Medicine, New York, New York, USA., Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.