Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis

Ankana Daga, Amar J. Majmundar, Daniela A. Braun, Heon Yung Gee, Jennifer A. Lawson, Shirlee Shril, Tilman Jobst-Schwan, Asaf Vivante, David Schapiro, Weizhen Tan, Jillian K. Warejko, Eugen Widmeier, Caleb P. Nelson, Hanan M. Fathy, Zoran Gucev, Neveen A. Soliman, Seema Hashmi, Jan Halbritter, Margarita Halty, Jameela A. Kari & 18 others Sherif El-Desoky, Michael A. Ferguson, Michael J.G. Somers, Avram Z. Traum, Deborah R. Stein, Ghaleb H. Daouk, Nancy M. Rodig, Avi Katz, Christian Hanna, Andrew L. Schwaderer, John A. Sayer, Ari J. Wassner, Shrikant Mane, Richard P. Lifton, Danko Milosevic, Velibor Tasic, Michelle A. Baum, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

Original languageEnglish
Pages (from-to)204-213
Number of pages10
JournalKidney International
Volume93
Issue number1
DOIs
Publication statusPublished - 2018 Jan 1

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Nephrocalcinosis
Exome
Nephrolithiasis
Mutation
Genes
Molecular Biology
Kidney
Recessive Genes
Consanguinity
Dominant Genes
Inborn Genetic Diseases
Age of Onset
Incidence

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Daga, Ankana ; Majmundar, Amar J. ; Braun, Daniela A. ; Gee, Heon Yung ; Lawson, Jennifer A. ; Shril, Shirlee ; Jobst-Schwan, Tilman ; Vivante, Asaf ; Schapiro, David ; Tan, Weizhen ; Warejko, Jillian K. ; Widmeier, Eugen ; Nelson, Caleb P. ; Fathy, Hanan M. ; Gucev, Zoran ; Soliman, Neveen A. ; Hashmi, Seema ; Halbritter, Jan ; Halty, Margarita ; Kari, Jameela A. ; El-Desoky, Sherif ; Ferguson, Michael A. ; Somers, Michael J.G. ; Traum, Avram Z. ; Stein, Deborah R. ; Daouk, Ghaleb H. ; Rodig, Nancy M. ; Katz, Avi ; Hanna, Christian ; Schwaderer, Andrew L. ; Sayer, John A. ; Wassner, Ari J. ; Mane, Shrikant ; Lifton, Richard P. ; Milosevic, Danko ; Tasic, Velibor ; Baum, Michelle A. ; Hildebrandt, Friedhelm. / Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. In: Kidney International. 2018 ; Vol. 93, No. 1. pp. 204-213.
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abstract = "The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4{\%} of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8{\%} of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.",
author = "Ankana Daga and Majmundar, {Amar J.} and Braun, {Daniela A.} and Gee, {Heon Yung} and Lawson, {Jennifer A.} and Shirlee Shril and Tilman Jobst-Schwan and Asaf Vivante and David Schapiro and Weizhen Tan and Warejko, {Jillian K.} and Eugen Widmeier and Nelson, {Caleb P.} and Fathy, {Hanan M.} and Zoran Gucev and Soliman, {Neveen A.} and Seema Hashmi and Jan Halbritter and Margarita Halty and Kari, {Jameela A.} and Sherif El-Desoky and Ferguson, {Michael A.} and Somers, {Michael J.G.} and Traum, {Avram Z.} and Stein, {Deborah R.} and Daouk, {Ghaleb H.} and Rodig, {Nancy M.} and Avi Katz and Christian Hanna and Schwaderer, {Andrew L.} and Sayer, {John A.} and Wassner, {Ari J.} and Shrikant Mane and Lifton, {Richard P.} and Danko Milosevic and Velibor Tasic and Baum, {Michelle A.} and Friedhelm Hildebrandt",
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Daga, A, Majmundar, AJ, Braun, DA, Gee, HY, Lawson, JA, Shril, S, Jobst-Schwan, T, Vivante, A, Schapiro, D, Tan, W, Warejko, JK, Widmeier, E, Nelson, CP, Fathy, HM, Gucev, Z, Soliman, NA, Hashmi, S, Halbritter, J, Halty, M, Kari, JA, El-Desoky, S, Ferguson, MA, Somers, MJG, Traum, AZ, Stein, DR, Daouk, GH, Rodig, NM, Katz, A, Hanna, C, Schwaderer, AL, Sayer, JA, Wassner, AJ, Mane, S, Lifton, RP, Milosevic, D, Tasic, V, Baum, MA & Hildebrandt, F 2018, 'Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis', Kidney International, vol. 93, no. 1, pp. 204-213. https://doi.org/10.1016/j.kint.2017.06.025

Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. / Daga, Ankana; Majmundar, Amar J.; Braun, Daniela A.; Gee, Heon Yung; Lawson, Jennifer A.; Shril, Shirlee; Jobst-Schwan, Tilman; Vivante, Asaf; Schapiro, David; Tan, Weizhen; Warejko, Jillian K.; Widmeier, Eugen; Nelson, Caleb P.; Fathy, Hanan M.; Gucev, Zoran; Soliman, Neveen A.; Hashmi, Seema; Halbritter, Jan; Halty, Margarita; Kari, Jameela A.; El-Desoky, Sherif; Ferguson, Michael A.; Somers, Michael J.G.; Traum, Avram Z.; Stein, Deborah R.; Daouk, Ghaleb H.; Rodig, Nancy M.; Katz, Avi; Hanna, Christian; Schwaderer, Andrew L.; Sayer, John A.; Wassner, Ari J.; Mane, Shrikant; Lifton, Richard P.; Milosevic, Danko; Tasic, Velibor; Baum, Michelle A.; Hildebrandt, Friedhelm.

In: Kidney International, Vol. 93, No. 1, 01.01.2018, p. 204-213.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis

AU - Daga, Ankana

AU - Majmundar, Amar J.

AU - Braun, Daniela A.

AU - Gee, Heon Yung

AU - Lawson, Jennifer A.

AU - Shril, Shirlee

AU - Jobst-Schwan, Tilman

AU - Vivante, Asaf

AU - Schapiro, David

AU - Tan, Weizhen

AU - Warejko, Jillian K.

AU - Widmeier, Eugen

AU - Nelson, Caleb P.

AU - Fathy, Hanan M.

AU - Gucev, Zoran

AU - Soliman, Neveen A.

AU - Hashmi, Seema

AU - Halbritter, Jan

AU - Halty, Margarita

AU - Kari, Jameela A.

AU - El-Desoky, Sherif

AU - Ferguson, Michael A.

AU - Somers, Michael J.G.

AU - Traum, Avram Z.

AU - Stein, Deborah R.

AU - Daouk, Ghaleb H.

AU - Rodig, Nancy M.

AU - Katz, Avi

AU - Hanna, Christian

AU - Schwaderer, Andrew L.

AU - Sayer, John A.

AU - Wassner, Ari J.

AU - Mane, Shrikant

AU - Lifton, Richard P.

AU - Milosevic, Danko

AU - Tasic, Velibor

AU - Baum, Michelle A.

AU - Hildebrandt, Friedhelm

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

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