VACTERL Association Etiology: The Impact of de novo and Rare Copy Number Variations

Abstract

Copy number variations (CNVs), either DNA gains or losses, have been found at common regions throughout the human genome. Most CNVs neither have a pathogenic significance nor result in disease-related phenotypes but, instead, reflect the normal population variance. However, larger CNVs, which often arise de novo, are frequently associated with human disease. A genetic contribution has long been suspected in VACTERL (Vertebral, Anal, Cardiac, TracheoEsophageal fistula, Renal and Limb anomalies) association. The anomalies observed in this association overlap with several monogenetic conditions associated with mutations in specific genes, e.g. Townes Brocks (SALL1), Feingold syndrome (MYCN) or Fanconi anemia. So far VACTERL association has typically been considered a diagnosis of exclusion. Identifying recurrent or de novo genomic variations in individuals with VACTERL association could make it easier to distinguish VACTERL association from other syndromes and could provide insight into disease mechanisms. Sporadically, de novo CNVs associated with VACTERL are described in literature. In addition to this literature review of genomic variation in published VACTERL association patients, we describe CNVs present in 68 VACTERL association patients collected in our institution. De novo variations (>30 kb) are absent in our VACTERL association cohort. However, we identified recurrent rare CNVs which, although inherited, could point to mechanisms or biological processes contributing to this constellation of developmental defects.

Structural and numerical changes of chromosome X in patients with esophageal atresia

“…19 Genetic aberration (eg pathogenic mutations), aneuploidies and structural chromosomal changes like translocations, inversions or copy number variations have previously been detected in B12.5% of patients in our cohort. This number will steadily increase, as it is expected that screening previously unresolved cases with whole exome sequencing or improved high-resolution microarray will identify both known and new causal genetic defects.…”

“…18,19 Triple X syndrome A triple X karyotype (see Supplementary Figure 1) was identified in three EA/TEF patients, resulting in an odds ratio for triple X syndrome of 11.3 (95% CI ¼ 3.6-35.2). All three were small for gestational age at birth (o5th percentile), with maternal ages ranging from almost 26 to 28 years.…”

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

“…15 Furthermore, de novo disease-causing CNVs have been described in patients with non-syndromic OA/TOF and the VACTERL association. 16 To determine the contribution of CNVs in OA/TOF aetiology, we profiled 375 Dutch, German and American OA/TOF patients in a comprehensive multiplatform array. We suggest that genomic de novo and rare overlapping CNVs contribute to isolated and non-isolated OA/TOF.…”

Ethical aspects of care in the newborn surgical patient

“…The information gained can be used to improve diagnostics and treatment of congenital anatomic anomalies. 9 Parents will also like to know whether their child will survive, and if so, what quality of life can be expected. This question forces us to keep evaluating both our surgical and medical treatment modalities.…”