A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies
Frontiers in Pediatrics
anorectal malformations; duane-radial ray syndrome; esophageal atresia; genetics-first; molecular inversion probe; Opitz-G/BBB syndrome; townes-brocks syndrome
© 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.
van de Putte, R., Dworschak, G., Brosens, E., Reutter, H., Marcelis, C., Acuna-Hidalgo, R., Kurtas, N., Steehouwer, M., Dunwoodie, S., Schmiedeke, E., Märzheuser, S., Schwarzer, N., Brooks, A., de Klein, A., Sloots, C., Tibboel, D., Brisighelli, G., Morandi, A., Bedeschi, M., Bates, M., Levitt, M., Peña, A., de Blaauw, I., Roeleveld, N., Brunner, H., van Rooij, I., & Hoischen, A. (2020). A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies. Frontiers in Pediatrics, 8 (). http://dx.doi.org/10.3389/fped.2020.00310