Abstract: TH-PO0112
Long-Read Genome Sequencing Improves Diagnostic Yield in Nephronophthisis and Steroid-Resistant Nephrotic Syndrome Cohorts
Session Information
- Integrative Genomics and Multi-Omics in Noncystic Genetic Kidney Disease
October 22, 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
- Marchuk, Daniel, Boston Children's Hospital, Boston, Massachusetts, United States
- Zion, Elena, Boston Children's Hospital, Boston, Massachusetts, United States
- Balbach, Maximilian, Boston Children's Hospital, Boston, Massachusetts, United States
- Truong, Tina, Boston Children's Hospital, Boston, Massachusetts, United States
- Nelson, Becca, Boston Children's Hospital, Boston, Massachusetts, United States
- Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
- Prakash, Chiranth M., Boston Children's Hospital, Boston, Massachusetts, United States
- Madariaga, Leire, Boston Children's Hospital, Boston, Massachusetts, United States
- Saida, Ken, Boston Children's Hospital, Boston, Massachusetts, United States
- Riedhammer, Korbinian M., Boston Children's Hospital, Boston, Massachusetts, United States
- Franken, Gijs A.C., Boston Children's Hospital, Boston, Massachusetts, United States
- Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
- Chung, Wendy K., Boston Children's Hospital, Boston, Massachusetts, United States
- Beggs, Alan H., Boston Children's Hospital, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background
To assess the added diagnostic yield of long-read genome sequencing (LR-GS) in kidney disease, we selected cohorts of proband-parent trios previously undiagnosed by exome sequencing (ES) for LR-GS using Oxford Nanopore Technologies or PacBio HiFi LR-GS platforms.
Methods
We selected two cohorts from kidney diseases with high pre-test probability of monogenic etiologies. PacBio HiFi LR-GS was completed for 24 families with a clinical diagnosis of nephronophthisis (NPHP), and Oxford Nanopore Technologies LR-GS was completed for 25 families with clinically diagnosed pediatric-onset steroid-resistant nephrotic syndrome (SRNS). We analyzed coding variants, intronic variants not captured on ES, short tandem repeats, and methylation data. Additionally, we "predicted" structural variants using the long-read sequencing data. All variants within 68 SRNS genes or 95 NPHP genes respectively were then assessed for potential pathogenicity. In addition, we evaluated all variants in a broader kidney disease gene list equivalent to a Renasight panel (Dahl JASN 34:2039, 2023) including 396 genes.
Results
New likely causative variants were found in 4/24 (~17%) families in the NPHP cohort and in 2/25 (8%) families with SRNS. In the NPHP cohort, three structural variants were identified that were previously missed by ES including a homozygous ~6kb deletion in NPHP4 with precise breakpoint resolution and a heterozygous deletion involving HFN1B. In the SRNS cohort, a second compound heterozygous pathogenic NUP93 intronic variant (c.2137-18G>A) that has been previously described with functional evidence of aberrant splicing (Rossanti J Hum Genet. 64:673, 2019) was identified in a patient with a previously detected protein-truncating NUP93 variant.
Conclusion
Our data support consideration of LR-GS in select nephrology populations with high likelihood of monogenic kidney disease. Specifically in patients with NPHP, LR-GS may increase the diagnostic yield through the resolution of complex pathogenic structural variants as these are common in many of these disorders.