Original articleDe novo microduplication at 22q11.21 in a patient with VACTERL association
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
References (26)
- et al.
Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients
Am. J. Hum. Genet.
(2003) Birth defects and oral contraceptives
Lancet
(1973)- et al.
Genomic disorders on 22q11
Am. J. Hum. Genet.
(2002) - et al.
Congenital anomalies including the VATER association in a patient with del(6)q deletion
J. Pediatr.
(1977) Microduplication 22q11.2: a new chromosomal syndrome
Eur. J. Med. Genet.
(2009)- et al.
Phenotypic expansion of the supernumerary derivative (22) chromosome syndrome: VACTERL and Hirschsprung’s disease
J. Pediatr. Surg.
(2007) - et al.
A case of VATER association associated with 9qh+
Genet. Couns.
(1996) - et al.
Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome
Hum. Mol. Genet.
(2007) - et al.
Caudal duplication syndrome with unilateral hypoplasia of the pelvis and lower limb and ventriculoseptal heart defect in a mother and features of VATER association in her child
Clin. Dysmorphol.
(2009) - et al.
Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH
Cytogenet. Genome Res.
(2009)
The spectrum of congenital anomalies of the VATER association: an international study
Am. J. Med. Genet.
Molecular characterisation of a supernumerary ring chromosome in a patient with VATER association
J. Med. Genet.
QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data
Nucleic Acids Res.
Cited by (51)
Prenatal phenotype of 22q11 micro-duplications: A systematic review and report on 12 new cases
2022, European Journal of Medical GeneticsPrenatal diagnosis of persistent left superior vena cava, polyhydramnios and a small gastric bubble in a fetus with VACTERL association
2021, Taiwanese Journal of Obstetrics and GynecologyCitation Excerpt :Corsella et al. [13] reported nine VACTERL association cases, and one of the fetuses exhibited PLSVC (1/9 = 11.1%). Schramm et al. [14] reported 12 cases with VACTERL association, one of which had PLSVC (1/12 = 8.3%). Agochukwu et al. [15] analyzed FOX1 and FOX gene mutations in 12 VACTER association cases, three of which also presented with PLSVC (3/12 = 25%).
Caudal Regression Syndrome—A Review Focusing on Genetic Associations
2020, World NeurosurgeryCitation Excerpt :The gene has thus been proposed as a potential contributor in the development of CRS.2 Polygenetic sequencing studies have also been performed to search for a genetic association.28,29 Molecular karyotyping of 12 patients with anorectal abnormalities contained within the clinical spectrum of CRS identified de novo microduplication at 22q11.2 in one patient who also exhibited cardinal features associated with VACTERL.28
Etiological concepts of gastrointestinal malformations/atresias
2023, Monatsschrift fur Kinderheilkunde