Kidney Week

Abstract: SA-PO0175

TRIO-Exome Sequencing Identifies Candidate Disease Variants in Early-Onset Kidney Stone Formers

Session Information

• Tubular, Metabolic, and Systemic Noncystic Genetic Kidney Diseases
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Reddy, Sanmayi, Boston Children's Hospital, Boston, Massachusetts, United States

Sanmayi Reddy, MS

• Gauntner, Victoria C., Boston Children's Hospital, Boston, Massachusetts, United States

Victoria C. Gauntner

• Baum, Michelle Amy, Boston Children's Hospital, Boston, Massachusetts, United States

Michelle Amy Baum, MD

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

• Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States

Amar J. Majmundar, MD, PhD

Background

A monogenic cause has been reported in 12-47% of pediatric kidney stone disease (KSD) patients within phenotype-enriched cohorts by next-generation sequencing. Genetic diagnoses were associated with younger age of onset. We hypothesized that novel monogenic causes of KSD could be identified by exome sequencing in children with early onset KSD.

Methods

21 families seen at Boston Children's Hospital from 2021-2025 were enrolled for research genomics for early onset KSD (<10 years) with (i) persistence >6 months, (ii) no secondary cause, and (iii) negative clinical KSD genetic testing when available. 14 families had TRIO-exome sequencing; an additional 3 had proband-only exome sequencing. For all proband exome data, variants within 54 KSD-associated genes and 162 phenocopy genes were identified. Beyond this virtual panel, recessive and de novo dominant inheritance models were applied genome-wide in TRIO data to detect variants in novel candidate genes. All variants were curated for rare population prevalence and in silico predicted impact on splicing or the protein product.

Results

Virtual panel analyses from exome data revealed 8 deleterious variants in 5/17 probands (29%) in 2 KSD genes and 3 phenocopy genes (1 autosomal recessive, 4 autosomal dominant). Only one likely pathogenic variant was observed in a single proband in the KSD gene SLC34A3; the remainder were variants of uncertain significance. TRIO analyses in exome data revealed 21 deleterious candidate variants in 8/14 families (57%) in 15 genes (6 autosomal recessive, 1 X-linked, 8 de novo dominant). Candidate genes were stratified by (i) selective nephron segment expression in published kidney single-cell RNA sequencing (scRNAseq) datasets and (ii) interaction with other candidates or KSD proteins within protein-protein interaction datasets (STRING). 3 candidate genes were selectively expressed within nephron tubular segments in kidney scRNAseq data (z-score % cell expression>1.5): SALL3 (distal convoluted tubule), DSEL (principal cell), TRIM26 (intercalated cell). One candidate:candidate PPI (DYNC2H1:DYNLL1) and three candidate:KSD PPI (GNB2:GNA11, GNB2:GNAS, RABL6:VPS33B) were identified.

Conclusion

TRIO-exome sequencing identifies candidate disease variants in a high fraction of early onset kidney stone formers.

Funding

• NIDDK Support