VACTERL Association and Related Disorders Panel

VACTERL association (also known as VATER association) is the nonrandom occurrence of three or more of the following birth defects: vertebral defects, anal atresia, cardiac defects, tracheal-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these major clinical features, VACTERL patients may less commonly have additional phenotypes including, but not limited to, genitourinary anomalies, single umbilical artery, strabismus, cloaca, and duodenal atresia (Solomon et al. 2010. PubMed ID: 20683998). Although there are many phenotypes of VACTERL that overlap with those of other congenital disorders, individuals with VACTERL do not have ophthalmologic anomalies, brain malformations, or hearing loss (Solomon. 2011. PubMed ID: 21846383); presence of any of these phenotypes may be indicative of an alternative condition.

The estimated incidence of VACTERL ranges from 1 in 10,000 to 1 in 40,000 infants, depending on the diagnostic criteria used (Solomon. 2018. PubMed ID: 30580478).

Disorders that share notable phenotype overlap with VACTERL association include Alagille syndrome, CHARGE syndrome, Currarino syndrome, Fanconi anemia, Feingold syndrome, VACTERL with hydrocephalus, Baller-Gerold syndrome, Holt-Oram syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, basal cell nevus syndrome, McKusick-Kaufman syndrome, TAR (thrombocytopenia with absent radius) syndrome, Fryns syndrome, MURCS (Müllerian duct aplasia, unilateral renal aplasia, and cervicothoracic somite dysplasia) association, hemifacial microsomia, and 22q11.2 deletion syndrome.

This test will not genetically confirm a VACTERL diagnosis. Rather, this test is intended to rule out potential alternative causes of the phenotypes observed in a patient suspected to have VACTERL. As many of the disorders that have phenotype overlap with VACTERL have known genetic components, genetic testing is crucial to establish a diagnosis per exclusionem (by exclusion). It has been recommended that a genetics-first approach is used for patients suspected of VACTERL to prevent misdiagnosis (van de Putte et al. 2020. PubMed ID: 32656166). Other advantages of testing may include reproductive planning and prenatal testing to follow up ultrasound results. 

VACTERL is an association of congenital malformations that occur together in a nonrandom fashion. However, the basis of each of these anomalies in an individual may not arise from a single cause, implying the inherent heterogeneity of this condition (Solomon. 2018. PubMed ID: 30580478). As such, limited information on genetic causes of VACTERL is currently available, though a small number of candidate genes with potential disease-causing variants have been identified in a restricted number of VACTERL cases.

This test includes candidate genes that have been associated with VACTERL association as well as genes that have been shown to be causative of other disorders that show significant phenotypic overlap. The genes on this panel have diverse functions; however, many of them have critical roles in development such as tissue-specific gene expression, modification of epigenetic marks, DNA repair, or regulation of cell growth. The genes on this panel also vary in their modes of inheritance. As a general trend, causative variants in many genes on this panel that cause autosomal dominant disorders often arise de novo. 

Copy number variants at various regions throughout the genome have been suggested to be causative of VACTERL association. Recurrent CNVs associated with VACTERL include 1p35.3 deletion, 8q24.3 duplication, 10q25.3 duplication, 17q23.3 deletion, 22q11.2 duplication, and Xp22.3 duplication (Brosens et al. 2013. PubMed ID: 23653573).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

As VACTERL association is heterogeneous and is diagnosed based on exclusion of phenotypically similar disorders, it is difficult to estimate the clinical sensitivity of this specific grouping of genes. In terms of the related syndromes, the clinical sensitivity (if known) varies, as shown in the summary table below.

This test is performed using Next-Generation Sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.0% average coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Exons 4-5 of RERE, exons 1-4 of NOTCH2, and exon 1 of MNX1 are not covered in this test due to high paralogy.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).