Atypical deletion of 22q11.2: Detection using the FISH TBX1 probe and molecular characterization with high-density SNP arrays

Beaujard, M; Chantot, Sandra; Dubois, M; Keren, Boris; Carpentier, Wassila; Mabboux, Philippe; Whalen, Sandra; Vodovar, M; Siffroi, Jean‐Pierre; Portnoı̈, Marie-France

doi:10.1016/j.ejmg.2009.05.010

Cited by 30 publications

(29 citation statements)

References 34 publications

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“…Targeted approaches, such as FISH, real-time PCR, analysis of polymorphic DNA markers, and quantitative fluorescent PCR, though well established and fast, are only effective in detecting common deletions [Fernán-dez et al, 2005;Oh et al, 2007;Molck et al, 2013;Vieira et al, 2013;Poirsier et al, 2016]. Thus, negative results may lead to false negative diagnosis, since atypical 22q11.2 deletions may occur [Beaujard et al, 2009;Molck et al, 2013].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Approach to Microdeletion Syndromes Based on 22q11.2 Investigation: Challenges in Four Cases

et al. 2017

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In the last few decades, different methods for the detection of genomic imbalances, such as the microdeletion syndromes, were developed. The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome and presents wide clinical heterogeneity. The aim of this study was to describe 4 unusual cases of genomic imbalances found in individuals with suspected microdeletion syndromes. Different methods were necessary to complete the diagnosis and to obtain information for genetic counseling. The study was retrospective and descriptive. From August 2014 to December 2015, 39 individuals were assessed using FISH and/or MLPA; in 15 cases, chromosomal microarray (CMA) analysis was carried out. Of 39 registered individuals, we found deletions in the 22q11.2 region in 10 individuals (8 individuals with 22q11.2DS and 2 individuals presenting with atypical deletions in the 22q11.2 region: 1 distal deletion and 1 central deletion). In one case with a typical 22q11.2 deletion, a familial balanced translocation was detected. In another case without a 22q11.2 deletion, a 6p duplication concomitant with a 9p deletion was detected by CMA. Clinical data are reported and diagnostic investigations are discussed. Essential aspects for the understanding of different diagnostic techniques of genomic imbalances are considered, and the 4 cases described underline the complexity and the difficulties involved in the diagnostic process. The approach is informative for clinical practice and may be applied in other contexts of genomic imbalance investigation in microdeletion syndromes.

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Section: Discussionmentioning

confidence: 99%

Diagnostic Approach to Microdeletion Syndromes Based on 22q11.2 Investigation: Challenges in Four Cases

et al. 2017

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“…The majority (90%) of the 22q11.2 deletions are of 3Mb (encompassing ~60 genes) occurring between LCR A and LCR D and often referred to as typically deleted region (TDR) while 8% are 1.5Mb in size (~28 genes) (LCR A-B). Some rare atypical deletions of shorter size and in variable locations have also been reported [5]. We have long been interested in 22q11.2DS as a model for studying the genetic contribution to psychiatric disorders and for exploring the correlation between the molecular characteristics of the deletion and the cognitive and psychiatric manifestations in the patients.…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype correlation in 22q11.2 deletion syndrome

et al. 2012

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BackgroundThe 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion.MethodsMolecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation.ResultsDeletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted.Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes.ConclusionsMLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms.Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

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“…Ninety% of cases of DGS and 70% of cases of VCF syndrome are caused by a 1.5 to 3.0 Mb hemizygous deletion of chromosome 22q11.2 [31]. More precisely, the strictly DiGeorge syndrome appears to be associated with only TBX1 deletion or mutations [32]. However, DGS-like phenotypes have also been reported in patients with deletions of chromosome 4q34.2-qter [33,34], 8p23-pter [34-36], 10p14-p15 [34,37-41], 17p13 [42] or 18q21 [43], chromosomes 4, 8 and 10 being the most frequently chromosomes described associated with DGS-like phenotype.…”

Section: Introductionmentioning

confidence: 99%

Utero-vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci

Morcel

Watrin

Pasquier

et al. 2011

Orphanet J Rare Dis

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BackgroundMayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. The uterovaginal aplasia is either isolated (type I) or more frequently associated with other malformations (type II or Müllerian Renal Cervico-thoracic Somite (MURCS) association), some of which belong to the malformation spectrum of DiGeorge phenotype (DGS). Its etiology remains poorly understood. Thus the phenotypic manifestations of MRKH and DGS overlap suggesting a possible genetic link. This would potentially have clinical consequences.MethodsWe searched DiGeorge critical chromosomal regions for chromosomal anomalies in a cohort of 57 subjects with uterovaginal aplasia (55 women and 2 aborted fetuses). For this candidate locus approach, we used a multiplex ligation-dependent probe amplification (MLPA) assay based on a kit designed for investigation of the chromosomal regions known to be involved in DGS.The deletions detected were validated by Duplex PCR/liquid chromatography (DP/LC) and/or array-CGH analysis.ResultsWe found deletions in four probands within the four chromosomal loci 4q34-qter, 8p23.1, 10p14 and 22q11.2 implicated in almost all cases of DGS syndrome.ConclusionUterovaginal aplasia appears to be an additional feature of the broad spectrum of the DGS phenotype. The DiGeorge critical chromosomal regions may be candidate loci for a subset of MRKH syndrome (MURCS association) individuals. However, the genes mapping at the sites of these deletions involved in uterovaginal anomalies remain to be determined. These findings have consequences for clinical investigations, the care of patients and their relatives, and genetic counseling.

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Atypical deletion of 22q11.2: Detection using the FISH TBX1 probe and molecular characterization with high-density SNP arrays

Cited by 30 publications

References 34 publications

Diagnostic Approach to Microdeletion Syndromes Based on 22q11.2 Investigation: Challenges in Four Cases

Diagnostic Approach to Microdeletion Syndromes Based on 22q11.2 Investigation: Challenges in Four Cases

Genotype-phenotype correlation in 22q11.2 deletion syndrome

Utero-vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci

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