ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

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

Authors

  • 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
Background

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).

Methods

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.

Results

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.

Conclusion

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.