Kidney Week

Abstract: PO1649

Copy Number Variation Analysis Increases Diagnostic Yield of Exome Sequencing and Facilitates the Identification of Genetic Causation for Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT)

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - 2
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Wu, Chen-Han Wilfred, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Chen-Han Wilfred Wu,

• Lim, Tze Yin, Columbia University, New York, New York, United States

Tze Yin Lim,

• Wang, Chunyan, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Chunyan Wang,

• Seltzsam, Steve, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Steve Seltzsam,

• Zheng, Bixia, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Bixia Zheng,

• Schierbaum, Luca M., Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Luca M. Schierbaum,

• Schneider, Sophia, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Sophia Schneider,

• Mann, Nina, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Nina Mann,

• Connaughton, Dervla M., Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Dervla M. Connaughton,

• Bauer, Stuart B., Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Stuart B. Bauer,

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi,

• Shril, Shirlee, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Shirlee Shril,

• Hildebrandt, Friedhelm, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children and adults under the age of 30 years. In a previous study, we detected by whole exome sequencing (WES) a causative mutation in a known gene for isolated or syndromic CAKUT in 13% of 232 families with CAKUT (JASN 29:2348, 2018). However, WES will not detect the presence of causative copy number variations (CNV), and CNVs have been detected in up to 16% of CAKUT (AJHG 9:987, 2012).

Methods

We performed a genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on the same cohort of 232 families with CAKUT in which we previously conducted WES analysis (JASN 29:2348, 2018). We evaluated the CNVs with the published predefined criteria (Nat Genet 51:957, 2019).

Results

In a subcohort of 170 families of the 232 family CAKUT cohort (JASN 29:2348, 2018) in whom sufficient DNA was available, we detected in 9 families (5.29%) a pathogenic CNV known to cause CAKUT. There was no competing variant by genome-wide CNV analysis, and there was no conflicting variant by WES analysis. In addition, we identified likely pathogenic CNVs in 1.76% of cases, potentially increasing the CNV diagnostic rate to 7.05%.

Conclusion

CNV analysis in this subcohort of 170 CAKUT families increased the diagnosis rate for genetic causes of CAKUT from 13% to 18% - 20%. We also identified three candidate loci that may cause CAKUT.