Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus

Xu, Yixin; Wang, Jian; Xu, Rang; Zhao, Pei; Wang, Xi-Ke; Sun, Hengjuan; Bao, Liming; Shen, Jie; Fu, Qin; Li, Fen; Kim, Sun

doi:10.1186/1471-2350-12-169

Cited by 26 publications

(27 citation statements)

References 32 publications

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“…Most importantly, our data indicate that all cases with the characteristic face exhibited 22q11.2 heterozygous 3-Mb or 1.5-Mb deletion, suggesting that characteristic face that commonly presents in the majority of Caucasian individuals [30] forms an indicative factor for direct diagnosis of 22q11.2 deletions in Chinese VCFS patients. There seems to be a discrepancy between the present study and the study of Xu et al [31], in which some of the 13 Chinese 22q11del patients did not show a characteristic face. This may be explained by that the patients in their study were mostly infants, whose facial characteristics might not have been yet recognizable, i.e., the phenotypes were not manifested yet.…”

Section: Discussioncontrasting

confidence: 99%

Characteristic Face: A Key Indicator for Direct Diagnosis of 22q11.2 Deletions in Chinese Velocardiofacial Syndrome Patients

Yang

et al. 2013

PLoS ONE

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Velocardiofacial syndrome (VCFS) is a disease in human with an expansive phenotypic spectrum and diverse genetic mechanisms mainly associated with copy number variations (CNVs) on 22q11.2 or other chromosomes. However, the correlations between CNVs and phenotypes remain ambiguous. This study aims to analyze the types and sizes of CNVs in VCFS patients, to define whether correlations exist between CNVs and clinical manifestations in Chinese VCFS patients. In total, 55 clinically suspected Chinese VCFS patients and 100 normal controls were detected by multiplex ligation-dependent probe amplification (MLPA). The data from MLPA and all the detailed clinical features of the objects were documented and analyzed. A total of 44 patients (80.0%) were diagnosed with CNVs on 22q11.2. Among them, 43 (78.2%) presented with 22q11.2 heterozygous deletions, of whom 40 (93.0%) had typical 3-Mb deletion, and 3 (7.0%) exhibited proximal 1.5-Mb deletion; no patient was found with atypical deletion on 22q11.2. One patient (1.8%) presented with a 3-Mb duplication mapping to the typical 3-Mb region on 22q11.2, while none of the chromosomal abnormalities in the MLPA kit were found in the other 11 patients and 100 normal controls. All the 43 patients with 22q11.2 deletions displayed characteristic face and palatal anomalies; 37 of them (86.0%) had cognitive or behavioral disorders, and 23 (53.5%) suffered from immune deficiencies; 10 patients (23.3%) manifested congenital heart diseases. Interestingly, all patients with the characteristic face had 22q11.2 heterozygous deletions, but no difference in phenotypic spectrum was observed between 3-Mb and 1.5-Mb deletions. Our data suggest that the characteristic face can be used as a key indicator for direct diagnosis of 22q11.2 deletions in Chinese VCFS patients.

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Section: Discussioncontrasting

confidence: 99%

Characteristic Face: A Key Indicator for Direct Diagnosis of 22q11.2 Deletions in Chinese Velocardiofacial Syndrome Patients

Yang

et al. 2013

PLoS ONE

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“…CTDs are a prominent part of the 22q11DS phenotype, with a frequency of approximately 75% in 22q11DS patients. Reports originating from Western countries associate 12.8-17.8% of CTDs to the del22q11, and our own work showed a lower incidence (6.13%) in Chinese CTDs patients [3]. The TBX1 gene, a member of a phylogenetically conserved T-box gene family of DNA-binding transcription factors, is mapped to the 22q11.2, and is hypothesised to be responsible for the cardiac phenotype of 22q11.2 deletion syndrome.…”

Section: Introductionmentioning

confidence: 87%

Novel TBX1loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion

Sun

Zhang

et al. 2014

BMC Med Genet

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BackgroundTBX1 and CRKL haploinsufficiency is thought to cause the cardiac phenotype of the 22q11.2 deletion syndrome. However, few unequivocal mutations of TBX1 and CRKL have been discovered in isolated conotrucal heart defects (CTDs) patients. The aim of the study was to screen the mutation of TBX1 and CRKL in isolated CTDs Chinese patients without 22q11.2 deletion and identify the pathomechanism of the missense mutations.MethodsWe enrolled 199 non-22q11.2 deletion patients with CTDs and 139 unrelated healthy controls. Gene sequencing were performed for all of them. The functional data of mutations were obtained by in vitro transfection and luciferase experiments and computer modelling.ResultsScreening of the TBX1 coding sequence identified a de novo missense mutation (c.385G → A; p.E129K) and a known polymorphism (c.928G → A; p.G310S). In vitro experiments demonstrate that the TBX1E129K variant almost lost transactivation activity. The TBX1G310S variant seems to affect the interaction of TBX1 with other factors. Computer molecular dynamics simulations showed the de novo missense mutation is likely to affect TBX1-DNA interaction. No mutation of CRKL gene was found.ConclusionsThese observations suggest that the TBX1 loss-of-function mutation may be involved in the pathogenesis of isolated CTDs. This is the first human missense mutation showing that TBX1 is a candidate causing isolated CTDs in Chinese patients without 22q11.2 deletion.

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“…Two of these genes displaying myogenic hypermethylation, PAX3 (a homeobox gene) and TBX1 (a T-box gene), encode transcription factors involved in various developmental pathways, including myogenesis 17 - 19 17 , 19 , 20 . In tested myogenic hypermethylated sites associated with these genes, we found that skeletal muscle was the only sample enriched in 5-hmC.…”

Section: Introductionmentioning

confidence: 94%

Early de novo DNA methylation and prolonged demethylation in the muscle lineage

Tsumagari¹,

et al. 2013

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Myogenic cell cultures derived from muscle biopsies are excellent models for human cell differentiation. We report the first comprehensive analysis of myogenesis-specific DNA hyper- and hypo-methylation throughout the genome for human muscle progenitor cells (both myoblasts and myotubes) and skeletal muscle tissue vs. 30 non-muscle samples using reduced representation bisulfite sequencing. We also focused on four genes with extensive hyper- or hypo-methylation in the muscle lineage (PAX3, TBX1, MYH7B/MIR499 and OBSCN) to compare DNA methylation, DNaseI hypersensitivity, histone modification, and CTCF binding profiles. We found that myogenic hypermethylation was strongly associated with homeobox or T-box genes and muscle hypomethylation with contractile fiber genes. Nonetheless, there was no simple relationship between differential gene expression and myogenic differential methylation, rather only for subsets of these genes, such as contractile fiber genes. Skeletal muscle retained ~30% of the hypomethylated sites but only ~3% of hypermethylated sites seen in myogenic progenitor cells. By enzymatic assays, skeletal muscle was 2-fold enriched globally in genomic 5-hydroxymethylcytosine (5-hmC) vs. myoblasts or myotubes and was the only sample type enriched in 5-hmC at tested myogenic hypermethylated sites in PAX3/CCDC140 andTBX1. TET1 and TET2 RNAs, which are involved in generation of 5-hmC and DNA demethylation, were strongly upregulated in myoblasts and myotubes. Our findings implicate de novo methylation predominantly before the myoblast stage and demethylation before and after the myotube stage in control of transcription and co-transcriptional RNA processing. They also suggest that, in muscle, TET1 or TET2 are involved in active demethylation and in formation of stable 5-hmC residues.

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Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus

Cited by 26 publications

References 32 publications

Characteristic Face: A Key Indicator for Direct Diagnosis of 22q11.2 Deletions in Chinese Velocardiofacial Syndrome Patients

Characteristic Face: A Key Indicator for Direct Diagnosis of 22q11.2 Deletions in Chinese Velocardiofacial Syndrome Patients

Novel TBX1loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion

Early de novo DNA methylation and prolonged demethylation in the muscle lineage

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