Microdeletions/duplications involving <i><scp>TBX1</scp></i> gene in fetuses with conotruncal heart defects which are negative for 22q11.2 deletion on fluorescence <i>in‐situ</i> hybridization

Chen, M.; Yang, Yu Shih; Shih, Jin-Chung; Lin, Wen‐Hsiang; Lee, D.-J.; Lin, Yu-Hsiang; Chou, Chien‐Hong; Cameron, Alan; Ginsberg, Norman; Chen, C.-A.; Lee, M.-L.; Ma, Gwo‐Chin

doi:10.1002/uog.12550

Cited by 31 publications

(27 citation statements)

References 36 publications

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“…Our findings agree with those reported by Chen et al [4], who used comparative genomic hybridization to analyze 45 fetal samples with conotruncal heart defects that were negative for del22q11.2 by FISH. Their results showed an 846-bp de novo deletion including exon 2 of the TBX1 gene in one patient with ToF.…”

Section: Discussionsupporting

confidence: 95%

Identification of Copy Number Variations in Isolated Tetralogy of Fallot

et al. 2015

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Tetralogy of Fallot (ToF) is one of the most common and severe congenital heart defects (CHD). Recently, unbalanced structural genomic variants or copy number variations (CNVs) were proposed to be involved in the etiology of many complex diseases, including CHDs. The aim of this study was to investigate the frequency of CNVs in a region with a high density of CNVs, 22q11.2, and other regions with CHD-related genes in a sample of 52 Mexican mestizo patients with isolated ToF and negative fluorescence in situ hybridization staining for 22q11. CNVs were studied using two multiplex ligation-dependent probe amplification (MLPA) kits, SALSA P250-B1® (DiGeorge gene region) and SALSA MLPA P311-A1® CHD-related gene regions (GATA4, NKX2-5, TBX5, BMP4, and CRELD1). The MLPA assay detected a de novo CNV deletion of the probes located in exons 2 and 7 of the TBX1 gene in one of the 52 patients studied; this result was confirmed by real-time quantitative polymerase chain reaction. This deletion was not present in the patient's parents and 104 chromosomes from healthy control subjects. Our results clearly suggest a possible etiologic association between the TBX1 deletion and the ToF in our patient.

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Section: Discussionsupporting

confidence: 95%

Identification of Copy Number Variations in Isolated Tetralogy of Fallot

et al. 2015

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“…Candidate critical genes for major features of DGS are thought to include HIRA , TBX1 and COMT [McDonaldMcGinn et al, 1999;Lindsay et al, 2001;Kessler-Icekson et al, 2002;Bearden et al, 2004;Prasad et al, 2008;Chen et al, 2014;Ogata et al, 2014]. CRKL is considered a candidate critical gene for the central deletions [Racedo et al, 2015], and MAPK1/ERK2 for the distal type I deletions [Saba-El-Leil et al, 2003;Binétruy et al, 2007;Newbern et al, 2008;Samuels et al, 2008].…”

Section: Variability Of Phenotypementioning

confidence: 99%

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

Burnside

2015

Cytogenet Genome Res

1,441

149

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Chromosome 22q11.21 contains a cluster of low-copy repeats (LCRs), referred to as LCR22A-H, that mediate meiotic non-allelic homologous recombination, resulting in either deletion or duplication of various intervals in the region. The deletion of the DiGeorge/velocardiofacial syndrome interval LCR22A-D is the most common recurrent microdeletion in humans, with an estimated incidence of ∼1:4,000 births. Deletion of other intervals in 22q11.21 have also been described, but the literature is often confusing, as the terms ‘proximal', ‘nested', ‘distal', and ‘atypical' have all been used to describe various of the other intervals. Individuals with deletions tend to have features with widely variable expressivity, even among families. This review concisely delineates each interval and classifies the reported literature accordingly.

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“…Previous studies have established the important role genetic risk factors serve in the pathogenesis of CTD (10)(11)(12)(13)(14)(15). The 22q11 deletion syndrome (22q11DS), also known as DiGeorge syndrome, is a chromosomal abnormality responsible for ~12% of conotruncal malformations (16)(17)(18)(19)(20)(21). Furthermore, mutations in a number of genes, particularly those encoding cardiac transcriptional factors, including NKX2-5, NKX2-6, GATA4, GATA5, GATA6, PITX2, HAND2, TBX5 and TBX20, are associated with CTD .…”

Section: Introductionmentioning

confidence: 99%

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

Zhang

Liu

et al. 2017

Exp Ther Med

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Abstract. Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the TBX1 gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of TBX1 in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified TBX1 sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic in silico. Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the ANF promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.

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Microdeletions/duplications involving TBX1 gene in fetuses with conotruncal heart defects which are negative for 22q11.2 deletion on fluorescence in‐situ hybridization

Abstract: Objectives Conotruncal heart defects (CTD) are associated with del22q11.2 syndrome, which is often diagnosed by fluorescence in-situ hybridization (FISH).

Cited by 31 publications

References 36 publications

Identification of Copy Number Variations in Isolated Tetralogy of Fallot

Identification of Copy Number Variations in Isolated Tetralogy of Fallot

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

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