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

Romy van de Putte, Gabriel C. Dworschak, Erwin Brosens, Heiko M. Reutter, Carlo L. M. Marcelis, Rocio Acuna-Hidalgo, Nehir E. Kurtas, Marloes Steehouwer, Sally L. Dunwoodie, Eberhard Schmiedeke, Stefanie Maerzheuser, Nicole Schwarzer, Alice S. Brooks, Annelies de Klein, Cornelius E. J. Sloots, Dick Tibboel, Giulia Brisighelli, Anna Morandi, Maria F. Bedeschi, Michael D. BatesMarc A. Levitt, Alberto Pena, Ivo de Blaauw, Nel Roeleveld, Han G. Brunner, Iris A. L. M. van Rooij, Alexander Hoischen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 inSALL1, SALL4, andMID1, 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.

Original languageEnglish
Article number310
Number of pages10
JournalFrontiers in pediatrics
Publication statusPublished - 23 Jun 2020


  • anorectal malformations
  • duane-radial ray syndrome
  • esophageal atresia
  • genetics-first
  • molecular inversion probe
  • Opitz-G
  • BBB syndrome
  • townes-brocks syndrome
  • FGF8

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