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Kidney Week

Abstract: PO1348

Reverse Phenotyping Facilitates Disease Allele Calling in Whole-Exome Sequencing of Patients with Congenital Anomalies of Kidney and Urinary Tract (CAKUT)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Seltzsam, Steve, Boston Children's Hospital, Boston, Massachusetts, United States
  • Wang, Chunyan, Boston Children's Hospital, Boston, Massachusetts, United States
  • Zheng, Bixia, Boston Children's Hospital, Boston, Massachusetts, United States
  • Connaughton, Dervla M., Boston Children's Hospital, Boston, Massachusetts, United States
  • Wu, Chen-Han Wilfred, Boston Children's Hospital, Boston, Massachusetts, United States
  • Schneider, Sophia, Boston Children's Hospital, Boston, Massachusetts, United States
  • Schierbaum, Luca M., Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children and young adults. To date, 174 genes are known to cause isolated or syndromic monogenic CAKUT. However, incomplete penetrance and broad phenotypic heterogeneity can impair disease allele identification, particularly in syndromic CAKUT. We hypothesized that the yield of a genetic diagnosis can be increased by combining whole exome sequencing (WES) with reverse phenotyping, in which the contributing physician is asked to examine a patient for signs/symptoms that may occur in the suspected clinical syndrome that results from the genetic variant detected by WES.

Methods

We conducted WES in an international cohort of 823 individuals with CAKUT from 732 unrelated families and evaluated WES data for variants in the 174 genes in which variants are known to cause isolated or syndromic CAKUT. In cases in whom the likely causative genotype suggested a syndromic phenotype that was not reported at enrollment, we conducted reverse phenotyping.

Results

In 84/732 (11.5%) families, we detected a likely causative variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of the 84 families (22.6%) with detection of a likely CAKUT-causing variant, reverse phenotyping yielded syndromic findings, thereby strengthening the genotype-phenotype correlation.

Conclusion

We conclude that employing reverse phenotyping in the evaluation of (facultative) syndromic CAKUT genes by WES provides an important tool to establish a more valid and specific diagnosis mitigating the broad phenotypic and genotypic heterogeneity of CAKUT.

Funding

  • Other NIH Support