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

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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
Volume11
Issue number4
DOIs
Publication statusPublished - 2016 Apr 7

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Nephrocalcinosis
Nephrolithiasis
Pediatrics
Mutation
Dominant Genes
Genes
Kidney
Abdominal Pain
Exons
Morbidity

All Science Journal Classification (ASJC) codes

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

Cite this

Braun, Daniela Anne ; Lawson, Jennifer Ashley ; Gee, Heon Yung ; Halbritter, Jan ; Shril, Shirlee ; Tan, Weizhen ; Stein, Deborah ; Wassner, Ari J. ; Ferguson, Michael A. ; Gucev, Zoran ; Fisher, Brittany ; Spaneas, Leslie ; Varner, Jennifer ; Sayer, John A. ; Milosevic, Danko ; Baum, Michelle ; Tasic, Velibor ; Hildebrandt, Friedhelm. / Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. In: Clinical Journal of the American Society of Nephrology. 2016 ; Vol. 11, No. 4. pp. 664-672.
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title = "Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis",
abstract = "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.",
author = "Braun, {Daniela Anne} and Lawson, {Jennifer Ashley} and Gee, {Heon Yung} and Jan Halbritter and Shirlee Shril and Weizhen Tan and Deborah Stein and Wassner, {Ari J.} and Ferguson, {Michael A.} and Zoran Gucev and Brittany Fisher and Leslie Spaneas and Jennifer Varner and Sayer, {John A.} and Danko Milosevic and Michelle Baum and Velibor Tasic and Friedhelm Hildebrandt",
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Braun, DA, Lawson, JA, Gee, HY, Halbritter, J, Shril, S, Tan, W, Stein, D, Wassner, AJ, Ferguson, MA, Gucev, Z, Fisher, B, Spaneas, L, Varner, J, Sayer, JA, Milosevic, D, Baum, M, Tasic, V & Hildebrandt, F 2016, 'Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis', Clinical Journal of the American Society of Nephrology, vol. 11, no. 4, pp. 664-672. https://doi.org/10.2215/CJN.07540715

Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. / Braun, Daniela Anne; Lawson, Jennifer Ashley; Gee, Heon Yung; Halbritter, Jan; Shril, Shirlee; Tan, Weizhen; Stein, Deborah; Wassner, Ari J.; Ferguson, Michael A.; Gucev, Zoran; Fisher, Brittany; Spaneas, Leslie; Varner, Jennifer; Sayer, John A.; Milosevic, Danko; Baum, Michelle; Tasic, Velibor; Hildebrandt, Friedhelm.

In: Clinical Journal of the American Society of Nephrology, Vol. 11, No. 4, 07.04.2016, p. 664-672.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis

AU - Braun, Daniela Anne

AU - Lawson, Jennifer Ashley

AU - Gee, Heon Yung

AU - Halbritter, Jan

AU - Shril, Shirlee

AU - Tan, Weizhen

AU - Stein, Deborah

AU - Wassner, Ari J.

AU - Ferguson, Michael A.

AU - Gucev, Zoran

AU - Fisher, Brittany

AU - Spaneas, Leslie

AU - Varner, Jennifer

AU - Sayer, John A.

AU - Milosevic, Danko

AU - Baum, Michelle

AU - Tasic, Velibor

AU - Hildebrandt, Friedhelm

PY - 2016/4/7

Y1 - 2016/4/7

N2 - 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.

AB - 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.

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JO - Clinical journal of the American Society of Nephrology : CJASN

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