title: Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis.
abstract: OBJECTIVE
  Nephrolithiasis is a prevalent condition that affects 10%-15% of adults in their lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal stone cohort has not yet been extensively studied.
  
  
  METHODS
  To determine the percentage of cases that can be explained molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a high-throughput exon sequencing analysis in an international cohort of 143 individuals <18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20). Over 7 months, all eligible individuals at three renal stone clinics in the United States and Europe were approached for study participation.
  
  
  RESULTS
  We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals who manifested later in life, causative mutations in dominant genes were more frequent.
  
  
  CONCLUSIONS
  We present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis.
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Daniela Anne
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Jennifer Ashley
authors.initials: JA
authors.lastname: Lawson
authors.affiliation: Division of Nephrology, Department of Medicine and Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea;
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Division of Nephrology, Department of Medicine and Division of Endocrinology/Nephrology, Department of Internal Medicine, University Clinic Leipzig, Leipzig, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stein
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Wassner
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ferguson
authors.affiliation: Department of Pediatric Nephrology, Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia;
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gucev
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Brittany
authors.initials: B
authors.lastname: Fisher
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Leslie
authors.initials: L
authors.lastname: Spaneas
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Varner
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.affiliation: Department of Pediatric Nephrology, Dialysis and Transplantation, Clinical Hospital Center Zagreb, University of Zagreb Medical School, Zagreb, Croatia; and.
authors.forename: Danko
authors.initials: D
authors.lastname: Milosevic
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Baum
authors.affiliation: Department of Pediatric Nephrology, Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia;
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Division of Nephrology, Department of Medicine and Howard Hughes Medical Institute, Chevy Chase, Maryland friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009397:Nephrocalcinosis / Q000453:epidemiology / Q000235:genetics*; D053040:Nephrolithiasis / Q000453:epidemiology / Q000235:genetics*; D015995:Prevalence
keywords: Europe; child; exons; genes, dominant; genetic renal disease; humans; hypercalciuria; kidney stones; mutation; nephrocalcinosis