Double outlet RV
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Chromosomal map of CHD genes and imbalances.Non syndromic associated genes overview
NKX2-5/NKX2.5 (1, 8.3%)
ACVR2B (1, 8.3%)
CFC1/CRYPTIC (1, 8.3%)
GDF1 (1, 8.3%)
FOG2/ZFPM2 (2, 16.7%)
NODAL (6, 50%)
In double outlet right ventricle (DORV) both the pulmonary artery and the aorta arise from the right ventricle. Normally, the pulmonary artery that carries blood to the lungs for oxygen arises from the right ventricle. The aorta, which carries oxygenated blood from the heart to the body, normally arises from the left ventricle. In most cases DORV is associated with a ventricular septal defect (DORV Fallot type), allowing oxygen rich blood of the left ventricle passing to the right ventricle, which pumps it to the aorta.
External references for Double outlet RV
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Genes for phenotype 01.01.04:Double outlet RV
Non-syndromic
| GDF1 
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- Support: unconfirmed: a single case report
- 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 were found amongst 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: 1/375 patients
- Comments: The patient population was not described for the number of DORVs present. It is therefore impossible to extrapolate what percentage of DORV patients carry a mutation. Karkera JD et al., 2007 performed mutation analysis of the TDGF1 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: unconfirmed: a single case report
- References: PMID:11799476 (population study with screening of similar CHD patients and normal controls )
- Inheritance: Sporadic double-outlet right ventricle (OMIM:217095)
- Incidence: 1/22 isolated DORV (and 1 polymorphism)
- Comments:
- Studies: (3)
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- Reference: PMID:11799476
- Incidence: 1/22 patients
- Comments: A maternally inherited alteration (G174del1) was identified in 1 subject with sporadic DORV. The patient's mother was not available for further clinical testing. This alteration was not identified in 200 normal chromosomes. Furthermore, the deletion is predicted to introduce a frameshift that disrupts the terminal membrane-associating domain and extends the open reading frame. Previous cellular-localization experiments and mutant-rescue assays indicate that the G174del1 alteration results in a functionally different protein product (Bamford et al., 2000). A missense alteration (R78W) was identified in 1 African American subject with DORV. Parental samples were not available for additional studies. Although not found in 200 random controls of unknown ethnicity, further examination of 154 normal controls of African American descent was performed, since, to date, all subjects identified as having this alteration have been of African American descent (Bamford et al., 2000). 21 were heterozygous for the R78W alteration, giving a carrier frequency of 13.6% (Goldmuntz E et al., 2002).
- Reference: PMID:11062482
- Incidence: 0/144 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. A R78W variant was found in 1 African American patient with dextrocardia, DORV, PA, complete AV canal, TAPVR, PDA, R-sided aortic arch, R-isomerism of lungs, intestinal malrotation and asplenia. This R78W change was not detected in over 300 chromosomes from control individuals of European descent, but was present in 4 of 136 chromosomes (3%) from African American control individuals (Bamford RN et al., 2000) .
- Reference: PMID:17445335
- Incidence: 0/18 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 8 polymorphisms in CFC1 in 9 of the 42 subjects, 3 synonymous coding variants, 3 non-synonymous coding variants (N21H, R47Q, and R78W), and 2 intronic variants in CFC1. In 6 subjects, multiple variants were found. The 3 non-synonymous were found in 5 out of 18 patients with DORV and heterotaxy: 1 patient with R78W, 4 patients with N21H and 3 patients with R47Q. The 3 non-synonymous variants are not located in conserved amino acids, or within conserved epidermal growth factor families or CFC motifs (Selamet Tierney ES et al., 2007).
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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: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: (2)
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- Reference: PMID:19553149
- Incidence: 3/375 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:19064609
- Incidence: 3/62 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 (62 with DORV). 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: likely: 2 or more patients (with CHD and a mutation in the candidate gene)
- References: 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: (1)
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- 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.
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Syndromic
| CFC1/CRYPTIC
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- Support: no good correlation between CHD type and candidate gene
- References: PMID:17445335 (population study with screening of similar CHD patients and normal controls )
- Syndromes: Double outlet RV (OMIM:217095) and heterotaxy
- Incidence: Mutation analysis was performed in 42 subjects with laterality defects and congenital cardiac disease. In 5 out of 18 patients with DORV and heterotaxy non-synonymous coding variants were found: R78W in 1, N21H in 4 and R47Q in 3 of these patients. In 3 of these patients multiple polymorphisms were found (Selamet Tierney et al., 2007).
- Comments: Bamford et al. found in total 4 unique nucleotide changes, not represented in over 200 normal controls.
- A heterozygous 334C→T transition corresponding to R112C in the EGF domain of exon 4. CHD type was not further specified.
- A heterozygous single-nucleotide deletion (522delC) corresponding to G174del1 at the beginning of the membrane-associating domain in exon 6 in two unrelated sporadic patients with TGA and heterotaxy (1 patient with L-isomerism and 1 with R-isomerism). The R112C and G174del1 mutations resulted in altered protein function, as demonstrated by aberrant cellular-localization and inability to rescue zebrafish one eyed pin head mutants, and were incompletely penetrant.
- A heterozygous 562C→T transition corresponding to R189C in exon 6 on the carboxy side of the membrane-associating domain in a patient with sporadic laterality defects and not further specified CHD. This residue is not conserved among EGF-CFC family members and the function of the protein seemed normal in all of the assays used.
- A heterozygous 232C→T transition predicting an R78W change was detected upstream of the EGF-domain in exon 3 in five unrelated sporadic patients of African American descent with various CHD and heterotaxy. This R78W change was not detected in over 300 chromosomes from control individuals of European descent, but was present in 4 of 136 chromosomes (3%) from African American control individuals. Since, to date, all subjects identified as having this alteration have been of African American descent, examination of 154 normal controls of African American descent was performed by Goldmuntz et al., 2002. 21 were heterozygous for the R78W alteration, giving a carrier frequency of 13.6%.
- Studies: (3)
[ show ] [ hide ]
- Reference: PMID:11799476
- Incidence: 1/22 patients
- Comments: A maternally inherited alteration (G174del1) was identified in 1 subject with sporadic DORV. The patient's mother was not available for further clinical testing. This alteration was not identified in 200 normal chromosomes. Furthermore, the deletion is predicted to introduce a frameshift that disrupts the terminal membrane-associating domain and extends the open reading frame. Previous cellular-localization experiments and mutant-rescue assays indicate that the G174del1 alteration results in a functionally different protein product (Bamford et al., 2000). A missense alteration (R78W) was identified in 1 African American subject with DORV. Parental samples were not available for additional studies. Although not found in 200 random controls of unknown ethnicity, further examination of 154 normal controls of African American descent was performed, since, to date, all subjects identified as having this alteration have been of African American descent (Bamford et al., 2000). 21 were heterozygous for the R78W alteration, giving a carrier frequency of 13.6% (Goldmuntz E et al., 2002).
- Reference: PMID:11062482
- Incidence: 0/144 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. A R78W variant was found in 1 African American patient with dextrocardia, DORV, PA, complete AV canal, TAPVR, PDA, R-sided aortic arch, R-isomerism of lungs, intestinal malrotation and asplenia. This R78W change was not detected in over 300 chromosomes from control individuals of European descent, but was present in 4 of 136 chromosomes (3%) from African American control individuals (Bamford RN et al., 2000) .
- Reference: PMID:17445335
- Incidence: 0/18 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 8 polymorphisms in CFC1 in 9 of the 42 subjects, 3 synonymous coding variants, 3 non-synonymous coding variants (N21H, R47Q, and R78W), and 2 intronic variants in CFC1. In 6 subjects, multiple variants were found. The 3 non-synonymous were found in 5 out of 18 patients with DORV and heterotaxy: 1 patient with R78W, 4 patients with N21H and 3 patients with R47Q. The 3 non-synonymous variants are not located in conserved amino acids, or within conserved epidermal growth factor families or CFC motifs (Selamet Tierney ES et al., 2007).
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| CHD7
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- Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene)
- References: PMID:16155193 (population study with screening of similar CHD patients and normal controls )
- Syndromes: CHARGE syndrome (OMIM:214800): Coloboma, Heart defect (ASD, VSD, and parachute mitral valve, ToF), Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness.
- Incidence: 69 mutations in CHD7 were found in 47 out of 107 index patients with CHARGE phenotype, 31 out of 47 patients had a congenital heart defect, of which 2 patients with double outlet right ventricle (Jongmans et al., 2006).
- Comments:
- Studies: (1)
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- Reference: PMID:16155193
- Incidence: 2/47 patients
- Comments: Jongmans et al. performed mutation analysis in series of 107 index patients with CHARGE phenotype and found 69 CHD7 mutations in 47 patients. Two mutations were recurrent, and all others were unique. We detected 31 nonsense, 17 frame shift, 13 splice site, and 8 missense mutations scattered throughout the gene. Thirty one (66%) patients had a congenital heart defect. Fourteen (30%) patients had major heart defects: 6 tetralogy of Fallot, 2 double-outlet right ventricle (one combined with hypoplastic left heart and AVSD), three isolated hypoplastic left heart syndrome, one hypoplastic right heart syndrome, one agenesis of the pulmonary valve combined with hypoplastic left heart, and one Shone’s complex. The other patients had solitary patent ductus arteriosus beyond infancy (n=3), patent ductus arteriosus combined with atrium septum defect, and/or ventricular septum defect (n=6) or a solitary septal defect (n=4).
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| BCOR
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- Support: unconfirmed: a single case report
- References: PMID:15004558 (population study with screening of similar CHD patients and normal controls )
- Syndromes: Oculofaciocardiodental Syndrome (OFCD) (OMIM:300166) is a distinct form of syndromic microphthalmia with congenital cataracts, narrow face, broad nasal tip with separated cartilage, cleft palate, and cardiac and dental anomalies (canine radiculomegaly, root dilacerations, oligodontia and retained deciduous teeth). OFCD is presumed to be inherited in an X-linked dominant pattern with male lethality.
- Incidence:
- Comments:
- Studies: (2)
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- Reference: PMID:15004558
- Incidence: 1/1 patients
- Comments: Ng D et al., 2004 sequenced BCOR in ten females from seven families with OFCD. Different mutations were found in all families (nonsense, frameshift, splicing and large deletion). In two sporadic cases for which DNA from parents was available, the mutations were de novo. In families OFCD5 and OFCD6, females in three and two generations, respectively, were affected and the mutations co-segregated. Double outlet right ventricle with large ASD, subpulmonary VSD and hypoplastic aortic arch was present in 1 out of 7 families with OFCD.
- Reference: PMID:19367324
- Incidence: 1/35 patients
- Comments: Hilton E et al., 2009 describes the phenotype of 35 females carrying a mutation in the BCOR gene. Congenital heart defects are present in 20 patients, with 85% (17/20) presenting a septal defect: atrial septal defects were present in 14 patients and ventricular septal defects in 6. One patient presented with double-outlet right ventricle in association with an ASD. The cardiac phenotype was not assessed in another 8 affected mutations carriers.
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Regions for phenotype 01.01.04:Double outlet RV
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Patients |
References |
OMIM |
Comments
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Translocations 01.01.04:Double outlet RV
| Region |
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Patients reports for 01.01.04:Double outlet RV
- case 2 Clinical data Phenotype
Automated text-mining genes found for 01.01.04:Double outlet RV
This page contributors
- Jeroen Breckpot - CME Leuven (Belgium) (association, mutation, study)
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