TY - JOUR
T1 - A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies
AU - van de Putte, Romy
AU - Dworschak, Gabriel C.
AU - Brosens, Erwin
AU - Reutter, Heiko M.
AU - Marcelis, Carlo L.M.
AU - Acuna-Hidalgo, Rocio
AU - Kurtas, Nehir E.
AU - Steehouwer, Marloes
AU - Dunwoodie, Sally L.
AU - Schmiedeke, Eberhard
AU - Märzheuser, Stefanie
AU - Schwarzer, Nicole
AU - Brooks, Alice S.
AU - de Klein, Annelies
AU - Sloots, Cornelius E.J.
AU - Tibboel, Dick
AU - Brisighelli, Giulia
AU - Morandi, Anna
AU - Bedeschi, Maria F.
AU - Bates, Michael D.
AU - Levitt, Marc A.
AU - Peña, Alberto
AU - de Blaauw, Ivo
AU - Roeleveld, Nel
AU - Brunner, Han G.
AU - van Rooij, Iris A.L.M.
AU - Hoischen, Alexander
PY - 2020/6/23
Y1 - 2020/6/23
N2 - 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.
AB - 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.
KW - anorectal malformations
KW - duane-radial ray syndrome
KW - esophageal atresia
KW - genetics-first
KW - molecular inversion probe
KW - Opitz-G/BBB syndrome
KW - townes-brocks syndrome
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U2 - 10.3389/fped.2020.00310
DO - 10.3389/fped.2020.00310
M3 - Article
AN - SCOPUS:85087558412
VL - 8
JO - Frontiers in Pediatrics
JF - Frontiers in Pediatrics
SN - 2296-2360
M1 - 310
ER -