Kidney International Reports (Mar 2025)
Trio Exome Sequencing in VACTERL Association
- Jasmina Ćomić,
- Erik Tilch,
- Korbinian M. Riedhammer,
- Melanie Brugger,
- Theresa Brunet,
- Katharina Eyring,
- Katharina Vill,
- Silke Redler,
- Velibor Tasic,
- Eberhard Schmiedeke,
- Frank-Mattias Schäfer,
- Nora Abazi-Emini,
- Ekkehart Jenetzky,
- Nicole Schwarzer,
- Anke Widenmann,
- Martin Lacher,
- Michael Zech,
- Sabine Grasshoff-Derr,
- Michaela Geßner,
- Carmen Kabs,
- Barbara Seitz,
- Andreas C. Heydweiller,
- Oliver Muensterer,
- Bärbel Lange-Sperandio,
- Udo Rolle,
- Johannes Schumacher,
- Matthias C. Braunisch,
- Riccardo Berutti,
- Heiko Reutter,
- Julia Hoefele
Affiliations
- Jasmina Ćomić
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Erik Tilch
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Korbinian M. Riedhammer
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Melanie Brugger
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Theresa Brunet
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Katharina Eyring
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Katharina Vill
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany
- Silke Redler
- Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
- Velibor Tasic
- University Children’s Hospital, Medical Faculty of Skopje, North Macedonia
- Eberhard Schmiedeke
- Clinic for Paediatric Surgery and Paediatric Urology, Klinikum Bremen-Mitte, Bremen, Germany
- Frank-Mattias Schäfer
- Department of Pediatric Surgery and Urology, Cnopf'sche Kinderklinik, Nürnberg, Germany
- Nora Abazi-Emini
- University Children’s Hospital, Medical Faculty of Skopje, North Macedonia
- Ekkehart Jenetzky
- Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany; Department of Pediatric and Adolescent Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
- Nicole Schwarzer
- SoMA, The German Patient Support Organization for Anorectal Malformations and Hirschsprung Disease, Munich, Germany
- Anke Widenmann
- Patient Organisation for Esophageal Diseases KEKS e.V., Stuttgart, Germany
- Martin Lacher
- Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
- Michael Zech
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Institute of Advanced Study, Technical University of Munich, Garching, Germany
- Sabine Grasshoff-Derr
- Pediatric Surgery Unit, Buergerhospital and Clementine Kinderhospital, Frankfurt, Germany
- Michaela Geßner
- KfH-Board of Trustees for Dialysis and Kidney Transplantation (KfH-Kuratorium für Dialyse und Nierentransplantatione.V.), Munich, Germany
- Carmen Kabs
- Department of Paediatrics Surgery, Muenchen KlinikgGmbH, Munich Clinic Schwabing, Munich, Germany
- Barbara Seitz
- KfH-Board of Trustees for Dialysis and Kidney Transplantation (KfH-Kuratorium für Dialyse und Nierentransplantatione.V.), Munich, Germany
- Andreas C. Heydweiller
- Department of General, Visceral, Vascular and Thoracic Surgery, Unit of Pediatric Surgery, University Hospital Bonn, Bonn, Germany
- Oliver Muensterer
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany
- Bärbel Lange-Sperandio
- Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany
- Udo Rolle
- Department of Pediatric Surgery and Pediatric Urology, University Hospital Frankfurt/M., Frankfurt am Main, Germany
- Johannes Schumacher
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany
- Matthias C. Braunisch
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Riccardo Berutti
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Heiko Reutter
- Department of Neonatology and Pediatric Intensive Care, University Erlangen-Nürnberg, Erlangen, Germany
- Julia Hoefele
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Institute of Human Genetics, University Hospital, Ludwig-Maximilians University, Munich, Germany; Correspondence: Julia Hoefele, Institute of Human Genetics, University Hospital, Ludwig-Maximilians University, Goethestr. 29, Munich 80336, Germany.
- DOI
- https://doi.org/10.1016/j.ekir.2024.12.006
- Journal volume & issue
-
Vol. 10,
no. 3
pp. 877 – 891
Abstract
Introduction: Currently, there is only limited data on monogenic causes of vertebral defects, anorectal malformations, cardiac defects, esophageal atresia or tracheoesophageal fistula, renal malformations, and limb defects (VACTERL) association. The aim of this study was to extend the spectrum of disease-causing variants in known genes, to determine the diagnostic yield of monogenic causes, and to identify candidate genes and rare variants by applying comprehensive genetic testing or rare variant burden. Methods: The total cohort comprised 101 affected individuals and their parents. Trio exome sequencing was only performed in 96 individuals and their parents because of DNA quality reasons and case-control gene and pathway burden tests were calculated and evaluated by quantile-quantile plots, principal component analysis plots and family-based association test (FBAT). Results: In 5 of 96 individuals, disease-causing variants in known genes or loci were identified to be associated with the following 4 disorders: Kabuki syndrome, Sotos syndrome, MELAS syndrome, and deletion syndrome encompassing TWIST1. In 91 individuals, no disease-causing variants were found. FBAT showed 14 significant variants, 2 significant genes (LOC645752 and ZNF417), and 8 significant pathways. Conclusion: This study shows that most individuals with VACTERL association do not have known discrete genetic syndromes, implying that pathomechanisms or variants not identifiable by exome sequencing may exist requiring further investigation.
Keywords
