Frontiers in Pediatrics (Jun 2020)

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

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

DOI
https://doi.org/10.3389/fped.2020.00310
Journal volume & issue
Vol. 8

Abstract

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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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