Copy Number Variation Analysis Facilitates Identification of Genetic Causation in Patients with Congenital Anomalies of the Kidney and Urinary Tract

Chen-Han Wilfred Wu; Tze Y Lim; Chunyan Wang; Steve Seltzsam; Bixia Zheng; Luca Schierbaum; Sophia Schneider; Nina Mann; Dervla M Connaughton; Makiko Nakayama; Amelie T van der Ven; Rufeng Dai; Caroline M Kolvenbach; Franziska Kause; Isabel Ottlewski; Natasa Stajic; Neveen A Soliman; Jameela A Kari; Sherif El Desoky; Hanan M Fathy; Danko Milosevic; Daniel Turudic; Muna Al Saffar; Hazem S Awad; Loai A Eid; Aravind Ramanathan; Prabha Senguttuvan; Shrikant M Mane; Richard S Lee; Stuart B Bauer; Weining Lu; Alina C Hilger; Velibor Tasic; Shirlee Shril; Simone Sanna-Cherchi; Friedhelm Hildebrandt

doi:10.1016/j.euros.2022.08.004

Copy Number Variation Analysis Facilitates Identification of Genetic Causation in Patients with Congenital Anomalies of the Kidney and Urinary Tract

Eur Urol Open Sci. 2022 Sep 1:44:106-112. doi: 10.1016/j.euros.2022.08.004. eCollection 2022 Oct.

Authors

Chen-Han Wilfred Wu^{1

2

3}, Tze Y Lim⁴, Chunyan Wang¹, Steve Seltzsam¹, Bixia Zheng¹, Luca Schierbaum¹, Sophia Schneider¹, Nina Mann¹, Dervla M Connaughton¹, Makiko Nakayama¹, Amelie T van der Ven¹, Rufeng Dai¹, Caroline M Kolvenbach¹, Franziska Kause¹, Isabel Ottlewski¹, Natasa Stajic⁵, Neveen A Soliman⁶, Jameela A Kari⁷, Sherif El Desoky⁷, Hanan M Fathy⁸, Danko Milosevic⁹, Daniel Turudic⁹, Muna Al Saffar^{1

10

11}, Hazem S Awad¹², Loai A Eid^{12

13}, Aravind Ramanathan¹⁴, Prabha Senguttuvan¹⁵, Shrikant M Mane¹⁶, Richard S Lee¹⁷, Stuart B Bauer¹⁷, Weining Lu¹⁸, Alina C Hilger¹⁹, Velibor Tasic²⁰, Shirlee Shril¹, Simone Sanna-Cherchi⁴, Friedhelm Hildebrandt¹

Affiliations

¹ Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Urology, Case Western Reserve University and University Hospitals, Cleveland, OH, USA.
³ Department of Genetics and Genome Sciences, Case Western Reserve University and University Hospitals, Cleveland, OH, USA.
⁴ Division of Nephrology, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Department of Pediatric Nephrology, Institute for Mother and Child Health Care, Belgrade, Serbia.
⁶ Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Cairo University, Egyptian Group for Orphan Renal Diseases, Cairo, Egypt.
⁷ Department of Pediatrics, King AbdulAziz University, Jeddah, Saudi Arabia.
⁸ Pediatric Nephrology Unit, University of Alexandria, Alexandria, Egypt.
⁹ Department of Pediatric Nephrology, University Hospital Center Zagreb, Zagreb, Croatia.
¹⁰ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
¹² Pediatric Nephrology Department, Dubai Hospital, Dubai, United Arab Emirates.
¹³ Department of Pediatrics, Dubai Medical College and Kidney Centre of Excellence, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates.
¹⁴ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
¹⁵ Department of Pediatric Nephrology, Dr. Mehta's Multi-Specialty Hospital, Chennai, India.
¹⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
¹⁷ Department of Urology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁸ Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA, USA.
¹⁹ Department of Pediatric and Adolescent Medicine, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany.
²⁰ Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia.

Abstract

Background: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease among children and adults younger than 30 yr. In our previous study, whole-exome sequencing (WES) identified a known monogenic cause of isolated or syndromic CAKUT in 13% of families with CAKUT. However, WES has limitations and detection of copy number variations (CNV) is technically challenging, and CNVs causative of CAKUT have previously been detected in up to 16% of cases.

Objective: To detect CNVs causing CAKUT in this WES cohort and increase the diagnostic yield.

Design setting and participants: We performed a genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on the same CAKUT cohort for whom WES was previously conducted.

Outcome measurements and statistical analysis: We evaluated and classified the CNVs using previously published predefined criteria.

Results and limitations: In a cohort of 170 CAKUT families, we detected a pathogenic CNV known to cause CAKUT in nine families (5.29%, 9/170). There were no competing variants on genome-wide CNV analysis or WES analysis. In addition, we identified novel likely pathogenic CNVs that may cause a CAKUT phenotype in three of the 170 families (1.76%).

Conclusions: CNV analysis in this cohort of 170 CAKUT families previously examined via WES increased the rate of diagnosis of genetic causes of CAKUT from 13% on WES to 18% on WES + CNV analysis combined. We also identified three candidate loci that may potentially cause CAKUT.

Patient summary: We conducted a genetics study on families with congenital anomalies of the kidney and urinary tract (CAKUT). We identified gene mutations that can explain CAKUT symptoms in 5.29% of the families, which increased the percentage of genetic causes of CAKUT to 18% from a previous study, so roughly one in five of our patients with CAKUT had a genetic cause. These analyses can help patients with CAKUT and their families in identifying a possible genetic cause.

Keywords: BAF, B allele frequency; CAKUT, Congenital anomalies of the kidneys and urinary tract; CNV, Copy number variations; Congenital anomalies of the kidney and urinary tract; Copy number variation; GD-CNV, Genomic disorders copy number variation; IRB, Institutional review board; Monogenic disease causation; Renal developmental; Vesicoureteral reflux; WES, Whole-exome sequencing; Whole-exome sequencing.

Abstract

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