Elsevier

European Journal of Medical Genetics

Volume 54, Issue 1, January–February 2011, Pages 9-13
European Journal of Medical Genetics

Original article
De novo microduplication at 22q11.21 in a patient with VACTERL association

https://doi.org/10.1016/j.ejmg.2010.09.001Get rights and content

Abstract

The non-random association of vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with esophageal atresia (TE), renal malformations (R), and limb defects (L) is termed VACTERL association. The aim of the present study was to identify microaberrations characterized by a loss or gain of genomic material that contribute to VACTERL association at a genome-wide level. Molecular karyotyping was performed in a cohort of 12 patients with anorectal malformations and at least two additional cardinal features of the VACTERL association. A de novo microduplication at chromosomal region 22q11.21 was identified in a patient presenting with three cardinal VACTERL features (V, A, R) and vesicoureteral reflux, penile hypospadias, caudal regression syndrome, and right-sided congenital equinovarus deformity.

Chromosomal region 22q11.2 is known for its susceptibility to rearrangements. Associated syndromes include the velo-cardio-facial and DiGeorge deletion syndromes, and the complementary 22q11.2 duplication syndrome. The findings of the present study extend the phenotypic spectrum of the 22q11.2 duplication syndrome, and indicate that it also predisposes to VACTERL association. We discuss the overlap between the phenotypic features of our patient and those reported for other 22q11.2 aberrations, and propose that dosage-sensitive loci for all of these phenotypic features may reside on 22q11.2.

Introduction

The non-random association of vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with esophageal atresia (TE), renal malformations (R), and limb defects (L) has been termed VACTERL association (MIM #192350) [14], [19]. Patients are classified as having VACTERL association when they display at least three of these cardinal features [5]. VACTERL occurs in approximately 1 in 7000 to 1 in 10,000 live births [5]. Nearly all reported cases have been sporadic. However, Solomon et al. [24] recently reported an increased prevalence of isolated VACTERL clinical features in first-degree relatives. Chromosomal abnormalities have been described in rare individual cases and proposed as possible causal factors [23]. These include: (i) deletions of distal 13q [25], ring chromosome 12 [6], and 6q [17]; (ii) duplication on 9q [1]; (iii) mutations in PTEN [22], HOXD13 [12], and ZIC3 [26]; and (iv) a mitochondrial c.3243A > G substitution [8].

The aim of the present study was to identify de novo microaberrations characterized by loss or gain of genomic material (i.e. copy number variants [CNVs]), which may contribute to VACTERL association at a genome-wide level. Molecular karyotyping with 657,366 single nucleotide polymorphisms (SNPs) was performed in 12 case-parent VACTERL trios. A de novo microduplication involving chromosomal region 22q11.21 was identified in one patient. These findings extend the phenotypic spectrum of the 22q11.2 duplication syndrome (MIM #608363), and indicate that a gene dosage effect involving the 22q11.2 region predisposes to the manifestation of VACTERL association.

Section snippets

Subjects

The study was approved by the local Ethics Committee and all families provided written informed consent. Families with supposed VACTERL association were contacted and recruited through the German self-help organization for patients with anorectal malformations (SoMA e.V.) and the Department of Pediatric Surgery and Pediatric Urology at the Children’s Hospital in Cologne, Germany. A total of 26 case-parent trios agreed to participate. Of these, 12 met the study inclusion criterion i.e. the

Results

Molecular karyotyping identified five possible de novo aberrations in four of the 12 patients. Four of these were not confirmed by qPCR (data not shown). The presence of a de novo microduplication at 22q11.21 was confirmed in one male patient (Case 1; Table 1). This had an estimated size of 2.51 Mb–2.54 Mb (Fig. 1). The first and last duplicated markers were rs450046 at genomic position 17,281,004, and rs140392 at genomic position 19,792,353, respectively (hg18). The flanking markers were

Discussion

It has been well established that chromosome region 22q11.2 is susceptible to rearrangements. This is attributable to nonallelic homologous recombination, which is mediated via eight region-specific low-copy repeats (LCR22s) [16]. Rearrangements involving these eight LCRs (LCR22-1–LCR22-8 [9], which may also be denoted alphabetically [13]), are associated with the following genomic disorders: (i) the VCFS/DGS (22q11.2 deletion syndrome, MIM 192430, 188400) [16], [20]; (ii) the complementary

Acknowledgements

We thank the patients and their parents for their cooperation. We also thank the German self-help organization for patients with anorectal malformations (SoMA e.V.). We thank Pia Uerdingen for her excellent technical assistance and Dr. Christine Schmael for her expert advice on the manuscript. C. S., M. D., M. M. N., M. L., and H. R. are members of the “Network for Systematic Investigation of the Molecular Causes, Clinical Implications, and Psychosocial Outcome of Congenital Uro-Rectal

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