Complete transposition of great arteries (IVS)
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Chromosomal map of CHD genes and imbalances.Non syndromic associated genes overview
MYH6 (1, 3.4%)
NKX2-5/NKX2.5 (1, 3.4%)
ZIC3 (1, 3.4%)
ACVR2B (1, 3.4%)
GDF1 (2, 6.9%)
THRAP2 (3, 10.3%)
CFC1/CRYPTIC (4, 13.8%)
FOXH1 (4, 13.8%)
NODAL (12, 41.4%)
Transposition of the great arteries (TGA) is an abnormality of the ventriculo-arterial connection, with the aorta originating from the morphologically right ventricle and the pulmonary artery from the morphologically left ventricle. Consequently the systemic and pulmonary circulations are in parallel, instead of being in series as in normal hearts. TGA can be associated with an intact ventricular septum or with a (un)restrictive ventricular septal defect (50%). Most infants with complete TGA have patent foramen ovale and a patent ductus arteriosus. In some cases TGA can be associated with left ventricular outflow tract obstruction (i.e. pulmonary stenosis) (25-30%).
External references for Complete transposition of great arteries (IVS)
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Genes for phenotype 01.01.02:Complete transposition of great arteries (IVS)
Non-syndromic
| THRAP2 
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- Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene)
- References: PMID:14638541 (population study with screening of similar CHD patients and normal controls )
- Inheritance: Dextro-looped transposition of the great arteries (OMIM:608808)
- Incidence: 3/97 isolated D-TGA
- Comments:
- Studies: (1)
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| GDF1
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- Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene)
- References: PMID:17924340 (population study with screening of similar CHD patients and normal controls )
- Inheritance: Inheritance of the mutations was not checked. The authors show the mutations cause a loss-of-function, and are absent from the normal population. They therefore at least present susceptibility factors for CHDs.
- Incidence: 8 mutations in 375 unrelated individuals with a wide spectrum of congenital cardiovascular malformations (Karkera JD et al., 2007).
- Comments:
- Studies: (1)
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- Reference: PMID:17924340
- Incidence: 2/375 patients
- Comments: The patient population was not described for the number of TGAs present. It is therefore impossible to extrapolate what percentage of TGA patients carry a mutation. Karkera JD et al., 2007 performed mutation analysis of the GDF1 gene in 375 unrelated individuals with a wide spectrum of non-syndromic congenital cardiovascular malformations, including TGA, tetralogy of Fallot (TOF), DORV, atrial septal defect (ASD), and interrupted aortic arch (IAA). Eight different putative disease-causing mutations were detected in only one proband per mutation: three of them presented with Tetralogy of Fallot, one with DORV, two with AVSD and two with transposition of the great arteries.
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| CFC1/CRYPTIC
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- Support: confirmed: 2 or more independent reports > 1% incidence
- References: PMID:11799476 (population study with screening of similar CHD patients and normal controls ) PMID:18538293 (population study with screening of similar CHD patients and normal controls )
- Inheritance: Isolated dextro-looped transposition of the great arteries (OMIM:608808), with or without heterotaxy.
- Incidence:
- Comments:
- Studies: (4)
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- Reference: PMID:11799476
- Incidence: 1/58 patients
- Comments: A novel, tandem duplication of the exon 4 splicedonor site (splice-site duplication) was identified in 1 patient with a D-TGA and an intact interventricular septum (and pyloric stenosis). The 20 duplicated base pairs contain the entire spliceosome recognition motif that anneals with U1 RNA. Either recognition site would be predicted to interact with the spliceosome with equal affinity. Utilization of the duplicated donor site predicts a frameshift, after the EGF motif, that would eliminate the CFC domain and the carboxy terminus. This alteration was not identified in 200 normal chromosomes. Parental samples were not available for evaluation. Goldmuntz et al. were unable to detect wild-type transcript in lymphoblast cell lines and thus could not further study the structure of the CFC1 transcript in this patient (Goldmuntz E et al., 2002).
- Reference: PMID:18538293
- Incidence: 1/62 patients
- Comments: Roessler et al. screened for mutations in GDF1, CFC1, TDGF1, FOXH1 and SMAD2 genes in 375 unrelated individuals with spectrum of congenital cardiovascular malformations. Potentially disruptive sequence alterations of the CFC1 gene were detected in 1 out of 62 patients with tranposition of the great arteries.
- Reference: PMID:17445335
- Incidence: 0/9 patients
- Comments: Direct sequence analysis of the coding sequence of CFC1 was performed in 42 subjects with laterality defects and congenital cardiac disease. Selamet Tierney et al. identified 3 synonymous coding variants, 3 non-synonymous coding variants (N21H, R47Q, and R78W), and 2 intronic variants in CFC1. The 3 non-synonymous variants are not located in conserved amino acids, or within conserved epidermal growth factor families or CFC motifs. The N21H variant was observed in 3 of 19 affected Caucasians, and the R47Q variant in another 2. Neither polymorphism was observed in Caucasian controls. The R47Q variant was found in 1 out of 9 patients with discordant ventriculo-arterial connection (TGA) (Selamet Tierney ES et al., 2007).
- Reference: PMID:11062482
- Incidence: 2/144 patients
- Comments: Bamford et al. studied 144 representing unrelated sporadic and familial cases of L-R axis abnormalities. In total 4 unique nucleotide changes were found (R112C, G174del1, R189C, R78W) not represented in over 200 normal controls. In two unrelated sporadic patients with TGA and heterotaxy (1 patient with L-isomerism and 1 with R-isomerism), a heterozygous single-nucleotide deletion (522delC) corresponding to G174del1 was detected at the beginning of the membrane-associating domain in exon 6. The deletion results in a frameshift that eliminates the membrane-associating domain and terminates 55 codons downstream of the deletion. The 522delC mutation was also present in one of the phenotypically normal parents of 1 patient. Cellular-localization experiments and mutant-rescue assays indicate that the G174del1 alteration results in a functionally different protein product. The G174del1 mutants are completely inactive in rescuing the zebrafish maternal-zygotic oep (MZoep) mutant phenotype, establishing that this nucleotide change abrogate the EGF-CFC activity of CFC1 (Bamford RN et al., 2000) .
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| NODAL
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- Support: confirmed: 2 or more independent reports > 1% incidence
- References: PMID:19553149 (population study with screening of similar CHD patients and normal controls ) PMID:19933292 (population study with screening of similar CHD patients and normal controls ) PMID:19064609 (population study with screening of similar CHD patients and normal controls )
- Inheritance: Significant reductions in the biological activity of NODAL alleles are detected among patients with congenital heart defects, lateraltity anomalies, and only rarely holoprosencephaly.
- Incidence:
- Comments:
- Studies: (3)
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- Reference: PMID:19553149
- Incidence: 1/375 patients
- Comments: Roessler et al., 2009 performed mutation analysis of the NODAL gene in 375 unrelated individuals with a wide spectrum of congenital heart defects and 400 subjects with holoprosencephaly. The most common malformation associated with defective NODAL signaling detected in this study involves the conotruncal malformations tetralogy of Fallot and, to a lesser extent, transposition of the great arteries and double outlet right ventricle. Six patients with Tetralogy of Fallot (ToF) carried two alleles with a significantly reduced biological activity of NODAL. The biological activity of the unique NODAL variant was not assessed in another two ToF patients. Three patients with DORV and one patient with TGA carried two alleles with a significantly reduced biological activity of NODAL.
- Reference: PMID:19933292
- Incidence: 1/7 patients
- Comments: De Luca et al., 2010 performed mutation analysis in a subset of known cardiac or heterotaxy genes (ZIC3, ACVR2B, LEFTYA, CFC1, NODAL, FOXH1, GDF1, CRELD1, GATA4 and NKX2.5) in 7 probands with familial non-syndromic transposition of the great arteries. A splice site mutation in the NODAL gene was detected in one proband. In addition to this variant, the patient harboured two non-synonymous changes in cis on the CFC1 gene. Both CFC1 variants have been reported at significant frequencies in unaffected African-American individuals.
- Reference: PMID:19064609
- Incidence: 10/95 patients
- Comments: Mohapatra et al., 2009 screened for NODAL mutations in 269 unrelated probands with either sporadic or familial heterotaxy or heterotaxy-related congenital cardiovascular defects (95 with d-TGA). This revealed four heterozygous missense variants, one in-frame insertion/deletion and two conserved splice site variants. One missense mutation was detected in 8 of the 82 unrelated Hispanic cases. All 14 mutation carriers presented with heterotaxy-related cardiovascular anomalies, 6 of them presented with additional abdominal situs abnormalities (one with right atrial isomerism). Transposition of the great arteries (d-TGA) was present in 10 out of the 14 mutation carriers, dextrocardia in 5 (one case with d-TGA and 2 with L-TGA (ventricular inversion)). In addition, 7 mutation carriers presented with a single ventricle, 8 with pulmonary atresia, 2 with pulmonic stenosis and 1 with a hypoplastic aortic arch. Other associated CHDs were: DORV in 3 cases, ASD type secundum in 8, AVSD in 2, common atrium in a single case and VSD in 5 cases. Vascular anomalies consisted of TAPVR in 4 cases, IVC abnormalities in 4 and left SVC in 2 cases.
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| ZIC3
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- Support: confirmed: 2 or more independent reports > 1% incidence
- References: PMID:10980576 (single case report ) PMID:17295247 (single case report ) PMID:19933292 (population study with screening of similar CHD patients and normal controls ) PMID:14681828 (population study with screening of similar CHD patients and normal controls )
- Inheritance: X-linked heterotaxy: ZIC3 mutations are found in males with familial or sporadic heterotaxy and heterotaxy-related congenital heart defects. Some mutations were found in patients (both male and female) with sporadic non-heterotaxy congenital heart defects.
- Incidence:
- Comments:
- Studies: (3)
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- Reference: PMID:19933292
- Incidence: 1/7 patients
- Comments: De Luca et al., 2010 performed mutation analysis in a subset of known cardiac or heterotaxy genes (ZIC3, ACVR2B, LEFTYA, CFC1, NODAL, FOXH1, GDF1, CRELD1, GATA4 and NKX2.5) in 7 probands with familial non-syndromic transposition of the great arteries. A heterozygous variant was detected in the FOXH1 gene in one girl with TGA. In addition to this variant, the patient harboured a heterozygous variant in the ZIC3 gene. Both variants were predicted in silico to be damaging.
- Reference: PMID:14681828
- Incidence: 4/4 patients
- Comments: Ware et al., 2004 performed mutation analysis of the ZIC3 gene in 20 familial and 145 sporadic cases of heterotaxy. In addition, the gene was sequenced in 29 patients with atrial septal or ventricular septal defects without evidence of a laterality disorder. Two nonsense and one missense mutation were identified in 3 male probands out of 20 families with familial X-linked heterotaxy. In each case, the mother of the proband was heterozygous for the mutation. Four of the 7 affected family members presented with a double-outlet right ventricle, 4 with pulmonic stenosis/atresia, 4 with transposition of the great arteries, 3 with a common atrioventricular canal, 3 with TAPVR, two with a hypoplastic left heart syndrome, two with a VSD, 1 with a right aortic arch and two with an abnormal inferior caval vein. In addition, a ZIC3 missense mutation was found in 1 girl with non-familial heterotaxy (out of 145 unrelated individuals). She presented with a L-TGA, ASD, VSD and pulmonic stenosis. Finally, one missense mutation was found in one out of 29 non-heterotaxy patients. This patient presented with an ASD and a pulmonic stenosis.
- Reference: PMID:10980576
- Incidence: 2/2 patients
- Comments: Megarbane et al., 2000 reported on a family with two maternal cousins presenting with transposition of the great arteries. In addition, one of the boys presented with a left superior vena cava, an atrial septal defect of the sinus venosus type, a large atrioventricular canal, a hypoplastic right ventricle, and severe subvalvar and valvar pulmonary stenosis. A mutation in the ZIC3 gene was detected in both of them. They did not show abdominal situs inversus (heterotaxy). Another maternal uncle of the two affected cousins also had the mutation but was not clinically affected.
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| FOXH1
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- Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene)
- References: PMID:18538293 (population study with screening of similar CHD patients and normal controls )
- Inheritance: sporadic dominant
- Incidence:
- Comments:
- Studies: (2)
[ show ] [ hide ]
- Reference: PMID:18538293
- Incidence: 3/62 patients
- Comments: Roessler et al. screened for mutations in GDF1, CFC1, TDGF1, FOXH1 and SMAD2 genes in 375 unrelated individuals with spectrum of congenital cardiovascular malformations. Potentially disruptive sequence alterations of the FOXH1 gene were detected in 3 out of 62 patients with tranposition of the great arteries.
- Reference: PMID:19933292
- Incidence: 1/7 patients
- Comments: De Luca et al., 2010 performed mutation analysis in a subset of known cardiac or heterotaxy genes (ZIC3, ACVR2B, LEFTYA, CFC1, NODAL, FOXH1, GDF1, CRELD1, GATA4 and NKX2.5) in 7 probands with familial non-syndromic transposition of the great arteries. A heterozygous variant was detected in the FOXH1 gene in one proband with TGA. In addition to this variant, the patient harboured a heterozygous variant in the ZIC3 gene. Both variants were predicted in silico to be damaging.
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Syndromic
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Regions for phenotype 01.01.02:Complete transposition of great arteries (IVS)
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Translocations 01.01.02:Complete transposition of great arteries (IVS)
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Patients reports for 01.01.02:Complete transposition of great arteries (IVS)
Automated text-mining genes found for 01.01.02:Complete transposition of great arteries (IVS)
This page contributors
- Jeroen Breckpot - CME Leuven (Belgium) (association, mutation, study)
- Sylvain Brohée - Katholieke Universiteit Leuven (Belgium) (Free text)
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