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Abstract: SA-PO614

Whole Exome Sequencing Frequently Detects a Monogenic Cause in Early Onset Nephrolithiasis and Nephrocalcinosis

Session Information

Category: Genetic Diseases of the Kidney

  • 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases


  • Daga, Ankana, Boston Children's Hospital, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Children''s Hospital, Somerville, Massachusetts, United States
  • Lawson, Jennifer A., University of Connecticut School of Medicine, Farmington, Connecticut, United States
  • Shril, Shirlee, Boston Childrens Hospital, Boston, Massachusetts, United States
  • Braun, Daniela A., Boston Children's Hospital, HMS, Boston, Massachusetts, United States
  • Baum, Michelle Amy, Boston Children Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

The incidence of Nephrolithiasis (NL) continues to rise. We previously detected a monogenic cause of NL in 20% of patients manifesting before the age of 25 years, and recently confirmed this high rate of monogenic causation (17%) in a pediatric cohort of patients by using a gene panel sequencing approach containing 30 known NL genes. We here employ whole exome sequencing (WES) rather than panel sequencing to identify monogenic causes of NL and/or nephrocalcinosis (NC).


Patients who had a history or renal ultrasound finding of at least one renal stone (NL) or NC before age 25 years were enrolled between 1/2014 to 12/2015. WES was performed on 51 families (65 affected individuals), and evaluated for causative mutations in 30 NL/NC genes. Deleteriousness of mutations was evaluated by pathogenicity prediction scores, evolutionary conservation, and prior reporting status of mutations.


63% were males, and the median age at presentation was 6 years (Range: 1 mo – 24 years). Of the 65 individuals, 32 had isolated NL, 22 had isolated NC, and 11 had both NL and NC. We detected a causative mutation in 15 out of 51 (29.4%) families. We detected a mutation in 7 recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in 1 dominant gene (SLC9A3R1), and in 1 gene (SLC34A1) with both recessive and dominant inheritance. 7 of the 19 different mutations were not previously described as disease causing. Median age of onset was significantly lower in patients in whom we detected a monogenic cause of NL/NC (3 yrs) vs. those without mutation detection (7 yrs) (p < 0.05). In one family we detected a causative mutation in one of 117 genes (CTNS) that represent phenocopies of NL-causing genes. Several factors that correlated with higher detection rate were younger age of onset of NL/NC (58%), presence of multiple affected in a family (41%), and presence of consanguinity (75%). In 9 of 15 families the genetic diagnosis led to specific implications for future clinical management and prevention of stone recurrence.


Thus, we established WES as an efficient approach towards a molecular genetic diagnosis in individuals with NL/NC who manifest before 25 years. Specific genetic diagnosis holds potential for personalization of the treatment plan.