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Abstract: FR-OR091

Clinical Exome Sequencing for Renal Disorders

Session Information

Category: Pathology and Lab Medicine

  • 1602 Pathology and Lab Medicine: Clinical

Authors

  • Wilson, Parker C., Washington University in St. Louis, Saint Louis, Missouri, United States
  • Love-gregory, Latisha, Washington University in St. Louis, Saint Louis, Missouri, United States
  • Corliss, Meagan, Washington University in St. Louis, Saint Louis, Missouri, United States
  • Mcnulty, Samantha N., Washington University in St. Louis, Saint Louis, Missouri, United States
  • Heusel, Jonathan, Washington University in St. Louis, Saint Louis, Missouri, United States
  • Gaut, Joseph, Washington University in St. Louis, Saint Louis, Missouri, United States
Background

Next-generation sequencing is a valuable tool for evaluating patients with suspected genetic renal disease. Clinical practice relies on targeted gene sets that are ordered based on patient phenotype and physician knowledge of the utility of genetic testing. We report the diagnostic yield of four clinically-established gene sets and employ a retrospective analysis of an expanded set of genes to characterize patients with pathogenic variants in genes that were not part of the ordered gene set.

Methods

In total, 324 patients underwent clinical exome sequencing based on physician-ordered gene sets for atypical hemolytic uremic syndrome (n=224), nephrotic syndrome/FSGS (n=56), cystic renal disease and nephronophthisis (n=26), Alport syndrome (n=13), or a custom panel (n=5). Also, patients referred for aHUS genetic testing were assessed for CFHR3-CFHR1 deletion by multiplex ligation-dependent probe amplification. Subsequently, all patients underwent retrospective analysis using an extended panel of 309 genes to detect additional potentially pathogenic variants according to ACMG 2015 guidelines.

Results

We identified 42 pathogenic and likely pathogenic variants in 97 of 324 patients and an additional 101 patients with a variant of uncertain significance. CFHR3-CFHR1 homozygous deletion was detected in 22 aHUS patients without a pathogenic or likely pathogenic variant. Overall, the diagnostic yield of the clinical gene sets was 20% and varied between groups (aHUS=18%, NS=16%, NPHP=46%, AS=23%). The extended gene set revealed 18 additional pathogenic or likely pathogenic variants and 8 patients with a high-risk APOL1 genotype, increasing the overall yield to 30%.

Conclusion

These results highlight the importance of a broad and collaborative approach between the clinical laboratory and their physician clients that employs additional analysis when the ordered gene set of kidney-disease-causing genes does not return a clinically meaningful result.

Funding

  • Clinical Revenue Support