Title

A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies

Authors

Romy van de Putte, Radboud University Nijmegen Medical Centre
Gabriel C. Dworschak, Universitäts-Klinikum Bonn und Medizinische Fakultät
Erwin Brosens, Erasmus MC
Heiko M. Reutter, Universitäts-Klinikum Bonn und Medizinische Fakultät
Carlo L.M. Marcelis, Radboud University Nijmegen Medical Centre
Rocio Acuna-Hidalgo, Radboud University Nijmegen Medical Centre
Nehir E. Kurtas, Radboud University Nijmegen Medical Centre
Marloes Steehouwer, Radboud University Nijmegen Medical Centre
Sally L. Dunwoodie, University of New South Wales (UNSW) Australia
Eberhard Schmiedeke, Klinikum Bremen-Mitte
Stefanie Märzheuser, Charité – Universitätsmedizin Berlin
Nicole Schwarzer, Self-Help Organisation for People with Anorectal Malformation-SoMA e.V.
Alice S. Brooks, Erasmus MC
Annelies de Klein, Erasmus MC
Cornelius E.J. Sloots, Erasmus MC Sophia Children's Hospital
Dick Tibboel, Erasmus MC Sophia Children's Hospital
Giulia Brisighelli, Baragwanath Hospital
Anna Morandi, Ospedale Maggiore Policlinico Milano
Maria F. Bedeschi, Ospedale Maggiore Policlinico Milano
Michael D. Bates, Dayton Children's Hospital
Marc A. Levitt, Dayton Children's Hospital
Alberto Peña, Dayton Children's Hospital
Ivo de Blaauw, Radboud University Nijmegen Medical Centre
Nel Roeleveld, Radboud University Nijmegen Medical Centre
Han G. Brunner, Radboud University Nijmegen Medical Centre
Iris A.L.M. van Rooij, Radboud University Nijmegen Medical Centre
Alexander Hoischen, Radboud University Nijmegen Medical Centre

Document Type

Journal Article

Publication Date

6-23-2020

Journal

Frontiers in Pediatrics

Volume

8

DOI

10.3389/fped.2020.00310

Keywords

anorectal malformations; duane-radial ray syndrome; esophageal atresia; genetics-first; molecular inversion probe; Opitz-G/BBB syndrome; townes-brocks syndrome

Abstract

© Copyright © 2020 van de Putte, Dworschak, Brosens, Reutter, Marcelis, Acuna-Hidalgo, Kurtas, Steehouwer, Dunwoodie, Schmiedeke, Märzheuser, Schwarzer, Brooks, de Klein, Sloots, Tibboel, Brisighelli, Morandi, Bedeschi, Bates, Levitt, Peña, de Blaauw, Roeleveld, Brunner, van Rooij and Hoischen. Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.

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