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Ćomić, J.* ; Tilch, E.* ; Riedhammer, K.M.* ; Brugger, M.* ; Brunet, T.* ; Eyring, K.* ; Vill, K.* ; Redler, S.* ; Tasic, V.* ; Schmiedeke, E.* ; Schäfer, F.M.* ; Abazi-Emini, N.* ; Jenetzky, E.* ; Schwarzer, N.* ; Widenmann, A.* ; Lacher, M.* ; Zech, M. ; Grasshoff-Derr, S.* ; Geßner, M.* ; Kabs, C.* ; Seitz, B.* ; Heydweiller, A.C.* ; Muensterer, O.* ; Lange-Sperandio, B.* ; Rolle, U.* ; Schumacher, J.* ; Braunisch, M.C.* ; Berutti, R.* ; Reutter, H.* ; Hoefele, J.*

Trio exome sequencing in VACTERL association.

Kidney Int. Rep., DOI: 10.1016/j.ekir.2024.12.006 (2025)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Burden Test ; Exome Sequencing ; Mitochondriopathy ; Vacterl Association ; Vacterl-like Phenotype ; Znf417
ISSN (print) / ISBN 2468-0249
e-ISSN 2468-0249
Journal Kidney international reports
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)