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      Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

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          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.


          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.


          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.

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          Author and article information

          Clin J Am Soc Nephrol
          Clin J Am Soc Nephrol
          Clinical Journal of the American Society of Nephrology : CJASN
          American Society of Nephrology
          7 April 2016
          19 January 2016
          : 11
          : 4
          : 664-672
          [* ]Division of Nephrology, Department of Medicine and
          [§ ]Division of Endocrinology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;
          []Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea;
          []Division of Endocrinology/Nephrology, Department of Internal Medicine, University Clinic Leipzig, Leipzig, Germany;
          Department of Pediatric Nephrology, Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia;
          []Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom;
          [** ]Department of Pediatric Nephrology, Dialysis and Transplantation, Clinical Hospital Center Zagreb, University of Zagreb Medical School, Zagreb, Croatia; and
          [†† ]Howard Hughes Medical Institute, Chevy Chase, Maryland
          Author notes

          D.A.B., J.A.L., and H.Y.G. contributed equally to this work.

          Correspondence: Dr. Friedhelm Hildebrandt, Division of Nephrology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Email: friedhelm.hildebrandt@ 123456childrens.harvard.edu
          PMC4822665 PMC4822665 4822665 07540715
          Copyright © 2016 by the American Society of Nephrology
          Page count
          Pages: 9
          Original Articles
          Custom metadata
          April 07, 2016


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