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. KariSherif 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

45 Scopus citations


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 (US)
Pages (from-to)204-213
Number of pages10
JournalKidney international
Issue number1
StatePublished - Jan 2018


  • monogenic cause
  • nephrocalcinosis
  • nephrolithiasis
  • whole exome sequencing

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    Daga, A., Majmundar, A. J., Braun, D. A., Gee, H. Y., Lawson, J. A., Shril, S., Jobst-Schwan, T., Vivante, A., Schapiro, D., Tan, W., Warejko, J. K., Widmeier, E., Nelson, C. P., Fathy, H. M., Gucev, Z., Soliman, N. A., Hashmi, S., Halbritter, J., Halty, M., ... Hildebrandt, F. (2018). Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney international, 93(1), 204-213. https://doi.org/10.1016/j.kint.2017.06.025