Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis

Daniela Anne Braun, Jennifer Ashley Lawson, Heon Yung Gee, Jan Halbritter, Shirlee Shril, Weizhen Tan, Deborah Stein, Ari J. Wassner, Michael A. Ferguson, Zoran Gucev, Brittany Fisher, Leslie Spaneas, Jennifer Varner, John A. Sayer, Danko Milosevic, Michelle Baum, Velibor Tasic, Friedhelm Hildebrandt

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88 Citations (Scopus)


Background and objectives 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. Design, setting, participants, & measurements 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.

Original languageEnglish
Pages (from-to)664-672
Number of pages9
JournalClinical Journal of the American Society of Nephrology
Issue number4
Publication statusPublished - 2016 Apr 7

Bibliographical note

Funding Information:
We thank the physicians and the participating families for their contribution. F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Warren E. Grupe Professor of Pediatrics. This research was supported by grants from the National Institutes of Health (DK1069274, DK1068306, and DK064614 to F.H.), and by the March of Dimes Foundation (6-FY11-241 to F.H.). H.Y.G. was supported by the Basic Science Research Program through the National Research Foundation of Korea by the Ministry of Education (2015R1D1A1A01056685).

Publisher Copyright:
© 2016 by the American Society of Nephrology.

All Science Journal Classification (ASJC) codes

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation


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