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Abstract: SA-PO546

Whole Genome Sequencing-Based Rare Copy-Number Variation Analysis in Patients With Proteinuric Kidney Disease

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Yoon, Jihoon, Boston Children's Hospital Department of Pediatrics, Boston, United States
  • Greenberg, Anya, Boston Children's Hospital Department of Pediatrics, Boston, Massachusetts, United States
  • Onuchic-Whitford, Ana C., Boston Children's Hospital Department of Pediatrics, Boston, Massachusetts, United States
  • Mcnulty, Michelle, Boston Children's Hospital Department of Pediatrics, Boston, Massachusetts, United States
  • Lee, Dongwon, Boston Children's Hospital Department of Pediatrics, Boston, Massachusetts, United States
  • Sampson, Matt G., Boston Children's Hospital Department of Pediatrics, Boston, Massachusetts, United States

Group or Team Name

  • NEPTUNE
Background

Copy-number variants (CNVs), which have relatively larger effects than single nucleotide variants, are major drivers of diverse diseases and phenotypes, including congenital anomalies of the kidney and urinary tract. However, their contributions to nephrotic syndrome (NS) have not been systematically investigated. We addressed this through a whole genome sequence (WGS) based analysis of CNV in 619 pediatric and adult patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE).

Methods

WGS was performed at a depth of 30x. High-confidence CNV in coding regions were identified by integrating multiple detection methods. We used ACMG/ClinGen criteria to identify pathogenic CNV. We selected ancestry-matched controls from putatively healthy controls from the 1000 Genome Project (1KGP) by performing PCA analysis. We assessed the genome-wide distribution of rare (MAF < 0.1%) CNVs in cases and controls. We annotated CNV for the presence of known Mendelian steroid resistant nephrotic syndrome (SRNS) genes and those in the Online Mendelian Inheritance in Man (OMIM) database.

Results

There were no CNV (>1kb) impacting coding regions of Mendelian SRNS genes. There were 10 large CNVs (>100 kb) in 9 patients (1.4%) predicted as pathogenic/likely pathogenic based on the ACMG/ClinGen criteria. Case-control analyses revealed no difference in rare CNV burden (MAF < 0.1%). However, NEPTUNE patients had a 1.2x increased burden of coding CNV than controls (1.23 folds, P=0.02). Gene Ontology (GO) analysis of OMIM genes in case-only CNVs, identified enrichment in the lipid metabolism processes, particularly “lipase activity” (GO:0016298, FDR=4.6×10-3).

Conclusion

CNV impacting known Mendelian SRNS genes do not appear to be a major form of disease-associate genetic architecture. The relevance to NS of the pathogenic CNV detected in these patients needs to be determined. Preliminary case-control analysis suggests that CNV located in genes related to lipid metabolism may contribute to proteinuric kidney disease. Further characterization of these CNVs and expansion to non-coding regions is required.

Funding

  • NIDDK Support