Rong Zhang1,2, Florian Marsch1, Franziska Kause1, Franziska Degenhardt1,2, Eeberhard Schmiedeke3, Stefanie Märzheuser4, Bernd Hoppe5, Haitham Bachour6, Thomas M Boemers7, Matthias Schäfer8, Nicole Spychalski8, Jörg Neser9, Johannes Leonhardt10, Ferdinand Kosch11, Benno Ure12, Barbara Gómez13, Martin Lacher14, Oliver J Deffaa14, Markus Palta15, Boris Wittekindt16, Katharina Kleine17, Andrea Schmedding18, Sabine Grasshoff-Derr19, Amelie van der Ven1,20, Stefanie Heilmann-Heimbach1,2, Nadine Zwink21, Ekkehart Jenetzky21,22,23, Michael Ludwig24, Heiko Reutter1,2,25. 1. Institute of Human Genetics, University of Bonn, Bonn, Germany. 2. Department of Genomics, Life & Brain Center, Bonn, Germany. 3. Department of Pediatric Surgery and Urology, Centre for Child and Youth Health, Klinikum Bremen-Mitte, Bremen, Germany. 4. Department of Pediatric Surgery, Campus Virchow Clinic, Charité University Hospital Berlin, Berlin, Germany. 5. Department of Pediatrics, University Medical Center, Bonn, Germany. 6. Department of Pediatric Surgery, University Hospital Bonn, Bonn, Germany. 7. Department of Pediatric Surgery and Urology, University Hospital Cologne, Cologne, Germany. 8. Department of Pediatric Surgery and Urology, Cnopf'sche Kinderklinik, Nürnberg, Germany. 9. Department of Pediatric Surgery, General Hospital, Chemnitz, Germany. 10. Department of Pediatric Surgery, St. Bernward-Krankenhaus, Hildesheim, Germany. 11. Department of Pediatric Surgery, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany. 12. Center of Pediatric Surgery Hannover, Hannover Medical School and Bult Children's Hospital, Hannover, Germany. 13. Department of Pediatric Surgery, Children's and Youth Hospital "Auf der Bult", Hannover, Germany. 14. Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany. 15. Department of Pediatric Surgery, Evangelisches Krankenhaus Hamm, Hamm, Germany. 16. Clinic for Pediatric and Adolescent Medicine, University Hospital, Frankfurt, Germany. 17. Department of Pediatric Surgery, Evangelisches Krankenhaus Oberhausen, Germany. 18. Department of Paediatric Surgery and Paediatric Urology, University Hospital of the Goethe-University Frankfurt/M, Frankfurt/M, Germany. 19. Department of Pediatric Surgery, Bürgerhospital, Frankfurt am Main, Germany. 20. Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 21. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. 22. Department for Child and Adolescent Psychiatry, Johannes Gutenberg-University, Mainz, Germany. 23. Child Centre Maulbronn, Hospital for Paediatric Neurology and Social Paediatrics, Maulbronn, Germany. 24. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. 25. Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.
Abstract
BACKGROUND: The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CF): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia, renal malformations (R), and limb defects (L). Patients presenting with at least three CFs are diagnosed as having VATER/VACTERL association while patients presenting with only two CFs are diagnosed as having VATER/VACTERL-like phenotypes. Recently, rare causative copy number variations (CNVs) have been identified in patients with VATER/VACTERL association and VATER/VACTERL-like phenotypes. METHODS: To detect further causative CNVs we performed array based molecular karyotyping in 75 VATER/VACTERL and 40 VATER/VACTERL-like patients. RESULTS: Following the application of stringent filter criteria, we identified 13 microdeletions and seven microduplications in 20 unrelated patients all of which were absent in 1,307 healthy inhouse controls (n < 0.0008). Among these, microdeletion at 17q12 was confirmed to be de novo. Three microdeletions at 5q23.1, 16q23.3, 22q11.21, and one microduplication at 10q11.21 were all absent in the available parent. Microdeletion of chromosomal region 22q11.21 was previously found in VATER/VACTERL patients rendering it to be causative in our patient. The remaining 15 CNVs were inherited from a healthy parent. CONCLUSION: In two of 115 patients' causative CNVs were found (2%). The remaining identified rare CNVs represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial VATER/VACTERL or VATER/VACTERL-like phenotypes. Birth Defects Research 109:1063-1069, 2017.
BACKGROUND: The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CF): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia, renal malformations (R), and limb defects (L). Patients presenting with at least three CFs are diagnosed as having VATER/VACTERL association while patients presenting with only two CFs are diagnosed as having VATER/VACTERL-like phenotypes. Recently, rare causative copy number variations (CNVs) have been identified in patients with VATER/VACTERL association and VATER/VACTERL-like phenotypes. METHODS: To detect further causative CNVs we performed array based molecular karyotyping in 75 VATER/VACTERL and 40 VATER/VACTERL-like patients. RESULTS: Following the application of stringent filter criteria, we identified 13 microdeletions and seven microduplications in 20 unrelated patients all of which were absent in 1,307 healthy inhouse controls (n < 0.0008). Among these, microdeletion at 17q12 was confirmed to be de novo. Three microdeletions at 5q23.1, 16q23.3, 22q11.21, and one microduplication at 10q11.21 were all absent in the available parent. Microdeletion of chromosomal region 22q11.21 was previously found in VATER/VACTERL patients rendering it to be causative in our patient. The remaining 15 CNVs were inherited from a healthy parent. CONCLUSION: In two of 115 patients' causative CNVs were found (2%). The remaining identified rare CNVs represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial VATER/VACTERL or VATER/VACTERL-like phenotypes. Birth Defects Research 109:1063-1069, 2017.
Authors: Olga M Moreno; Ana I Sánchez; Angélica Herreño; Gustavo Giraldo; Fernando Suárez; Juan Carlos Prieto; Ana Shaia Clavijo; Mercedes Olaya; Yaris Vargas; Javier Benítez; Jordi Surallés; Adriana Rojas Journal: Mol Syndromol Date: 2020-11-11
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