Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

Autor:	Ahram DF; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Lim TY; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Ke J; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Jin G; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Verbitsky M; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Bodria M; Division of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Kil BH; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Chatterjee D; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Piva SE; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Marasa M; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Zhang JY; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Cocchi E; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Caridi G; Division of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Laboratory on Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Gucev Z; Medical Faculty of Skopje, University Children's Hospital, Skopje, Macedonia., Lozanovski VJ; Medical Faculty of Skopje, University Children's Hospital, Skopje, Macedonia.; Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany., Pisani I; Unità Operativa Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy., Izzi C; Division of Nephrology, Department of Obstetrics and Gynecology, ASST Spedali Civili of Brescia, Brescia, Italy., Savoldi G; Medical Genetics Laboratory, ASST-Spedali Civili, Brescia, Italy., Gnutti B; Medical Genetics Laboratory, ASST-Spedali Civili, Brescia, Italy., Capone VP; Department of Medicine, Division of Nephrology, Columbia University, New York, New York.; Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy., Morello W; Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy., Guarino S; Department of Woman and Child and of General and Specialized Surgery, Università degli Studi della Campania 'Luigi Vanvitelli,' Naples, Italy., Esposito P; Department of Internal Medicine, University of Genoa, Genova, Italy.; Unit of Nephrology, IRCCS San Martino Polyclinic Hospital, Genoa, Italy., Lambert S; Yale School of Medicine/Yale New Haven Health System, New Haven, Connecticut., Radhakrishnan J; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Appel GB; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Uy NS; Division of Pediatric Nephrology, Department of Pediatric, NewYork-Presbyterian Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, New York., Rao MK; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Canetta PA; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Bomback AS; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Nestor JG; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Hays T; Department of Pediatrics, Division of Neonatology, Columbia University, New York, New York., Cohen DJ; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Finale C; Nephrology, Dialysis and Renal Transplantation Unit, Azienda Ospedaliera Universitaria Ospedali Riuniti Umberto I, Lancisi, Salesi of Ancona, Ancona, Italy., Wijk JAEV; Department of Pediatric Nephrology, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands., La Scola C; Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero Universitaria Sant'Orsola-Malpighi, Bologna, Italy., Baraldi O; Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Tondolo F; Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Di Renzo D; 'Spirito Santo' Hospital of Pescara, Pediatric Surgery of 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy., Jamry-Dziurla A; Polish Registry of Congenital Malformations, Chair and Department of Medical Genetics, University of Medical Sciences, Poznan, Poland., Pezzutto A; Nephrology and Dialysis Unit, Department of Medicine, SS Annunziata Hospital, 'G. d'Annunzio' University, Chieti, Italy., Manca V; Department of Pediatric Urology, Azienda Ospedaliera Brotzu, Cagliari, Italy., Mitrotti A; Department of Medicine, Division of Nephrology, Columbia University, New York, New York.; Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Santoro D; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy., Conti G; Department of Pediatric Nephrology, Azienda Ospedaliera Universitaria 'G. Martino,' Messina, Italy., Martino M; Pediatric Nephrology and Dialysis Unit, Pediatric Hospital 'Giovanni XXIII,' Bari, Italy., Giordano M; Pediatric Nephrology and Dialysis Unit, Pediatric Hospital 'Giovanni XXIII,' Bari, Italy., Gesualdo L; Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Zibar L; Department of Nephrology, University Hospital Merkur, Zagreb, Croatia.; Faculty of Medicine, University Josip Juraj Strossmayer in Osijek, Osijek, Croatia., Masnata G; Department of Pediatric Urology, Azienda Ospedaliera Brotzu, Cagliari, Italy., Bonomini M; Nephrology and Dialysis Unit, Department of Medicine, SS Annunziata Hospital, 'G. d'Annunzio' University, Chieti, Italy., Alberti D; Pediatric Surgery, University of Brescia, Brescia, Italy., La Manna G; IRCCS Azienda Ospedaliera di Bologna, Nephrology, Dialysis and Kidney Transplant Unit, St. Orsola University Hospital, Bologna, Italy., Caliskan Y; Division of Nephrology, Saint Louis University School of Medicine, Saint Louis, Missouri., Ranghino A; Nephrology, Dialysis and Renal Transplantation Unit, Azienda Ospedaliera Universitaria Ospedali Riuniti Umberto I, Lancisi, Salesi of Ancona, Ancona, Italy., Marzuillo P; Department of Woman and Child and of General and Specialized Surgery, Università degli Studi della Campania 'Luigi Vanvitelli,' Naples, Italy., Kiryluk K; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Krzemień G; Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland., Miklaszewska M; Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland., Lin F; Division of Pediatric Nephrology, Department of Pediatric, NewYork-Presbyterian Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, New York., Montini G; Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.; Department of Clinical Sciences and Community Health, Giuliana and Bernardo Caprotti Chair of Pediatrics, University of Milano, Milano, Italy., Scolari F; Division of Nephrology and Dialysis, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili of Brescia, Brescia, Italy., Fiaccadori E; Unità Operativa Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy., Arapović A; Department of Pediatrics, University Hospital of Split, Split, Croatia.; School of Medicine, University of Split, Split, Croatia., Saraga M; Department of Pediatrics, University Hospital of Split, Split, Croatia.; School of Medicine, University of Split, Split, Croatia., McKiernan J; Department of Urology, Columbia University Irving Medical Center, New York, New York., Alam S; Department of Urology, Columbia University Irving Medical Center, New York, New York.; Division of Pediatric Urology, MUSC Health-University Medical Center, Charleston, South Carolina., Zaniew M; Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland., Szczepańska M; Department of Pediatrics, FMS in Zabrze, Medical University of Silesia, Katowice, Poland., Szmigielska A; Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland., Sikora P; Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland., Drożdż D; Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland., Mizerska-Wasiak M; Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland., Mane S; Yale Center for Mendelian Genomics (YCMG), New Haven, Connecticut., Lifton RP; Yale Center for Mendelian Genomics (YCMG), New Haven, Connecticut., Tasic V; Medical Faculty of Skopje, University Children's Hospital, Skopje, Macedonia., Latos-Bielenska A; Polish Registry of Congenital Malformations, Chair and Department of Medical Genetics, University of Medical Sciences, Poznan, Poland., Gharavi AG; Department of Medicine, Division of Nephrology, Columbia University, New York, New York., Ghiggeri GM; Division of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Laboratory on Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Materna-Kiryluk A; Polish Registry of Congenital Malformations, Chair and Department of Medical Genetics, University of Medical Sciences, Poznan, Poland., Westland R; Department of Pediatric Nephrology, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands., Sanna-Cherchi S; Department of Medicine, Division of Nephrology, Columbia University, New York, New York.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2023 Jun 01; Vol. 34 (6), pp. 1105-1119. Date of Electronic Publication: 2023 Mar 30.
DOI:	10.1681/ASN.0000000000000132
Abstrakt:	Significance Statement: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. Background: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. Methods: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). Results: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. Conclusions: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis. (Copyright © 2023 by the American Society of Nephrology.)
Databáze:	MEDLINE
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