Exome sequencing highlights copy number variants in nephrolithiasis and nephrocalcinosis

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Exome sequencing highlights copy number variants in nephrolithiasis and nephrocalcinosis

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Co-author 1

Ken Saida kensai524@gmail.com Boston Children's Hospital Department of Pediatrics Boston United States *

Co-author 2

Amar Majmundar Amar.Majmundar1@childrens.harvard.edu Boston Children's Hospital Department of Pediatrics Boston United States -

Co-author 3

Friedhelm Hildebrandt Friedhelm.Hildebrandt1@childrens.harvard.edu Boston Children's Hospital Department of Pediatrics Boston United States -

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Introduction

Monogenic causes are common in early-onset nephrolithiasis/nephrocalcinosis (NL/NC), yet a substantial fraction of patients remain without a molecular diagnosis. Many prior studies emphasized single-nucleotide variants (SNVs), leaving exon-level copy-number variants (CNVs) under-detected. We assessed the diagnostic yield of an exome-based workflow that integrates CNV detection.

Methods

Exome sequencing was performed in 310 affected individuals from 290 unrelated families with NL/NC onset <25 years. Primary analysis applied a virtual 30-gene panel of established NL/NC genes with integrated SNV and exon-level CNV calling. Unsolved families underwent an exploratory 184-gene phenocopy/kidney-related screen (tubulopathy and ciliopathy sets). Variants were interpreted under ACMG/AMP guidelines with segregation and orthogonal CNV confirmation when available.

Results

The 30-gene analysis identified pathogenic/likely pathogenic variants in 42/290 families (14.5%), comprising SNVs 34/290 (11.7%), CNVs 6/290 (2.1%), and combined SNV+CNV 2/290 (0.7%). The exploratory 184-gene screen yielded 9 additional families (3.1%), for an overall yield of 51/290 (17.6%). Among the 42 diagnoses from the established-gene analysis, cystinuria (SLC3A1, SLC7A9) accounted for 33% (14/42), primary hyperoxaluria (AGXT, HOGA1) for 21% (9/42), and distal renal tubular acidosis (ATP6V1B1, ATP6V0A4) for 19% (8/42); the remainder comprised calcium/phosphate metabolism disorders and other rare conditions. CNV calling resolved single-exon and multi-exon deletions, including compound SNV+CNV genotypes that SNV-only workflows would miss.

Conclusion

An exome-based, tiered workflow that incorporates exon-level CNV detection increases diagnostic yield in early-onset NL/NC and clarifies underlying allelic architecture. Standardizing ES-CNV workflows and using genome-scale assays when needed will enhance detection and precision care.

Kewords