title: Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis.
abstract: Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Michelle
authors.initials: M
authors.lastname: Baum
authors.affiliation: Institute of Genetic Medicine, International Centre for Life and.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Hynes
authors.affiliation: Institute of Genetic Medicine, International Centre for Life and Epithelial Research Group, Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Rice
authors.affiliation: Epithelial Research Group, Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: David T
authors.initials: DT
authors.lastname: Thwaites
authors.affiliation: Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia; and.
authors.forename: Zoran S
authors.initials: ZS
authors.lastname: Gucev
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Brittany
authors.initials: B
authors.lastname: Fisher
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Leslie
authors.initials: L
authors.lastname: Spaneas
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Porath
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Division of Endocrinology, Department of Medicine, and.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Wassner
authors.affiliation: Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Caleb P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia; and.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Institute of Genetic Medicine, International Centre for Life and john.sayer@newcastle.ac.uk friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.affiliation: Division of Nephrology, Department of Medicine, Howard Hughes Medical Institute, Chevy Chase, Maryland john.sayer@newcastle.ac.uk friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000328:Adult; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D006801:Humans; D020125:Mutation, Missense; D009397:Nephrocalcinosis / Q000235:genetics*; D053040:Nephrolithiasis / Q000235:genetics*
keywords: Bartter syndrome; human genetics; hypercalciuria; kidney stones; molecular genetics; renal tubular acidosis