Steve Seltzsam1, Chunyan Wang2, Bixia Zheng1, Nina Mann1, Dervla M Connaughton1, Chen-Han Wilfred Wu3, Sophia Schneider1, Luca Schierbaum1, Franziska Kause1, Caroline M Kolvenbach1, Makiko Nakayama1, Rufeng Dai1, Isabel Ottlewski1, Ronen Schneider1, Konstantin Deutsch1, Florian Buerger1, Verena Klämbt1, Youying Mao1, Ana C Onuchic-Whitford4, Camille Nicolas-Frank1, Kirollos Yousef1, Dalia Pantel5, Ethan W Lai1, Daanya Salmanullah1, Amar J Majmundar1, Stuart B Bauer6, Nancy M Rodig1, Michael J G Somers1, Avram Z Traum1, Deborah R Stein1, Ankana Daga1, Michelle A Baum1, Ghaleb H Daouk1, Velibor Tasic7, Hazem S Awad8, Loai A Eid8, Sherif El Desoky9, Mohammed Shalaby9, Jameela A Kari9, Hanan M Fathy10, Neveen A Soliman11, Shrikant M Mane12, Shirlee Shril1, Michael A Ferguson1, Friedhelm Hildebrandt13. 1. Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA. 2. Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Nephrology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China. 3. Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA. 4. Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 5. Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany. 6. Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA. 7. Medical Faculty Skopje, University Children's Hospital, Skopje, North Macedonia. 8. Pediatric Nephrology Department, Dubai Hospital, Dubai, United Arab Emirates. 9. Department of Pediatrics, King Abdul Aziz University, Jeddah, Saudi Arabia; Pediatric Nephrology Center of Excellence, Department of Pediatrics, King Abdul Aziz University, Jeddah, Saudi Arabia. 10. Pediatric Nephrology Unit, University of Alexandria, Alexandria, Egypt. 11. Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt. 12. Department of Genetics, Yale University School of Medicine, New Haven, CT. 13. Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
Abstract
PURPOSE: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. METHODS: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. RESULTS: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation. CONCLUSION: We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.
PURPOSE: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. METHODS: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. RESULTS: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation. CONCLUSION: We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.
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