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

Abstract

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. van de Putte et al. Genetics-First Approach in Congenital Anomaly Patients 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.

Common pathogenesis for sirenomelia, OEIS complex, limb‐body wall defect, and other malformations of caudal structures

“…A variety of pathogenic mechanisms by which sirenomelia, VACTERL association, OEIS complex, and LBWD arise have been championed by different observers. Deficiency of the embryonic disc, deficiency of the caudal mesoderm, early amnion rupture and amniotic bands, intrauterine constraint, vascular disruption, vitelline vascular steal, gene mutations, and genomic imbalance are among the suggested mechanisms (Gajzer et al, 2015; Hartwig et al, 1989; Hunter et al, 2011; Miller, 1983; Stevenson et al, 1986; Streeter, 1930; Van Allen et al, 1987; van de Putte et al, 2020).…”

Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas

“…Previously, deleterious variation in the disease genes (SOX2, CHD7, MID1, SALL1, MYCN, EFTUD2, and the FANC genes) candidate genes has been determined in patients of which sufficient DNA material was available. Variants have either been determined with a Molecular Inversion Probe (MIP) gene panel [82], Sanger sequencing or Whole Exome Sequencing (WES) during routine diagnostic procedures. We did not have sufficient DNA of patient 3, 23 and 28.…”

Heritability and De Novo Mutations in Oesophageal Atresia and Tracheoesophageal Fistula Aetiology

“…In Table 1, established genes from animal models and human OA/TOF syndromes are depicted alongside their probability of loss of function, probability of intolerance to bi-allelic variation, missense z-score, and synonymous z-scores. This table was modified after [24,25], and a substantial portion of these genes was evaluated in a large cohort of patients with OA-and VACTERL-associated anomalies using a Molecular Inversion Probe Candidate gene screening [32]. Interestingly, Screening VACTERL patients including those with OA/TOF as well as exome and genome sequencing of patients did not result in high de novo rates in these genes [26,27,29,32].…”