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

Schramm, Christian; Draaken, Markus; Bartels, Enrika; Boemers, Thomas M.; Aretz, Stefan; Brockschmidt, Felix F.; Nöthen, Markus M.; Ludwig, Michael; Reutter, Heiko

doi:10.1016/j.ejmg.2010.09.001

Cited by 56 publications

(49 citation statements)

References 25 publications

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“…The patient affected with all of the 6 core VACTERL features and her mother had a 22q11.2 micro duplication overlapping 1.4 Mb of the de novo duplication in a VACTERL patient described by Schramm et al [2011]. This patient had vertebral fusion, anal atresia, right-sided duplicated kidney, and additional non-VACTERL deformations.…”

Section: Cnvs Identified In the Rotterdam Vacterl Cohortmentioning

confidence: 99%

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

et al. 2012

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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.

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Section: Cnvs Identified In the Rotterdam Vacterl Cohortmentioning

confidence: 99%

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

et al. 2012

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“…Forty-one patients presented with three or more CFs of the VATER/VACTERL association, while six patients presented with only two, with or without further anomalies (VATER/VACTERL-like phenotype). 1 For the mutation-sequencing analysis, an additional 59 patients with VATER/VACTERL association and 60 patients with VATER/-VACTERL-like phenotype recruited within Germany were added to the patient sample, of which 18 patients were previously described in Schramm et al 15,16 An additional 26 patients with VATER/ VACTERL association were recruited within the AGORA project and were added to the sample for the mutation-sequencing analysis. The AGORA project is run within the Netherlands and patients are being recruited by pediatric surgeons and clinical geneticists of the Radboud University, Nijmegen Medical Centre, Nijmegen, the Netherlands.…”

Section: Subjects and Dna Isolationmentioning

confidence: 99%

“…None of the patients used for array-based analysis has been reported in our previous studies. 15,16 To optimize for detection of de novo CNVs, we only included patients with a negative family history of the disease. Forty-one patients presented with three or more CFs of the VATER/VACTERL association, while six patients presented with only two, with or without further anomalies (VATER/VACTERL-like phenotype).…”

Section: Subjects and Dna Isolationmentioning

confidence: 99%

“…In accordance with this, previous studies have identified several de novo chromosomal microaberrations, which are likely to be disease causing. [5][6][7][8][9][10][11][12][13][14][15][16] However, none of these de novo chromosomal microaberrations has led to the identification of a disease-causing gene and the etiology in most cases is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association

et al. 2013

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“…There is substantial evidence that genetic factors contribute to the development of these malformations; in particular, CNV studies in sporadic patients have identified de novo events that occur in specific chromosomal regions (Bartels et al, 2011;Boocock & Donnai, 1987;Boyadjiev et al, 2004;Cuschieri & EUROCAT Working Group, 2001;Draaken et al, 2010;Falcone et al, 2007;Keppler-Noreuil, 2001;Ludwig et al, 2009;Marcelis et al, 2011;Schramm et al, 2011aSchramm et al, , 2011bShapiro et al, 1984). We hypothesized that CNVs affecting coding regions that occur after twinning might contribute to discordance in MZ twin pairs with ARM or the BEEC.…”

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confidence: 99%

CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

et al. 2013

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Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.

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

Cited by 56 publications

References 25 publications

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

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

De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association

CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

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