Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT.

Autor:	Seltzsam S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Wang C; 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., Zheng B; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Mann N; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Connaughton DM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Wu CW; 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., Schneider S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Schierbaum L; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Kause F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Kolvenbach CM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Nakayama M; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Dai R; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Ottlewski I; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Schneider R; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Deutsch K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Buerger F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Klämbt V; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Mao Y; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Onuchic-Whitford AC; 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., Nicolas-Frank C; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Yousef K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Pantel D; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Lai EW; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Salmanullah D; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Majmundar AJ; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Bauer SB; Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Rodig NM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Somers MJG; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Traum AZ; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Stein DR; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Daga A; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Baum MA; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Daouk GH; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Tasic V; Medical Faculty Skopje, University Children's Hospital, Skopje, North Macedonia., Awad HS; Pediatric Nephrology Department, Dubai Hospital, Dubai, United Arab Emirates., Eid LA; Pediatric Nephrology Department, Dubai Hospital, Dubai, United Arab Emirates., El Desoky S; 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., Shalaby M; 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., Kari JA; 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., Fathy HM; Pediatric Nephrology Unit, University of Alexandria, Alexandria, Egypt., Soliman NA; Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt., Mane SM; Department of Genetics, Yale University School of Medicine, New Haven, CT., Shril S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Ferguson MA; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Hildebrandt F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Feb; Vol. 24 (2), pp. 307-318. Date of Electronic Publication: 2021 Nov 30.
DOI:	10.1016/j.gim.2021.09.010
Abstrakt:	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. Competing Interests: Conflict of Interest F.H. is a cofounder and Scientific Advisory Committee member of and holds stocks in Goldfinch-Bio. All other authors declare no conflicts of interest. (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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