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

van de Putte, Romy and Dworschak, Gabriel C. and Brosens, Erwin and Reutter, Heiko M. and Marcelis, Carlo L. M. and Acuna-Hidalgo, Rocio and Kurtas, Nehir E. and Steehouwer, Marloes and Dunwoodie, Sally L. and Schmiedeke, Eberhard and Märzheuser, Stefanie and Schwarzer, Nicole and Brooks, Alice S. and de Klein, Annelies and Sloots, Cornelius E. J. and Tibboel, Dick and Brisighelli, Giulia and Morandi, Anna and Bedeschi, Maria F. and Bates, Michael D. and Levitt, Marc A. and Peña, Alberto and de Blaauw, Ivo and Roeleveld, Nel and Brunner, Han G. and van Rooij, Iris A. L. M. and Hoischen, Alexander (2020) A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies. Frontiers in Pediatrics, 8. p. 310. ISSN 2296-2360

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Link to published document: http://doi.org/10.3389/fped.2020.00310


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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine, Health and Life Sciences > School of Medicine
Depositing User: Repository Administrator
Date Deposited: 21 Jul 2020 22:44
Last Modified: 28 Oct 2021 02:09
URI: http://eprints.victorchang.edu.au/id/eprint/1013

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