Position or morphology of thoraco-abdominal organs abnormal

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  Chromosomal map of CHD genes and imbalances.

Non syndromic associated genes overview

LEFTY2 (2, 9.1%)

ACVR2B (3, 13.6%)

ZIC3 (8, 36.4%)

NODAL (9, 40.9%)

situs inversus totalis

[edit] Synopsys

Heterotaxy or situs ambiguus, is a complex congenital disorder characterized by the disruption of the normal left-right (LR) asymmetry of the thoraco-abdominal organs. Heterotaxy includes complex cardiac and vascular abnormalities that are thought to emerge from partial or complete reversal of heart tube looping, LR patterning of the atria or the failure of asymmetric remodeling of symmetric embryonic structures.
Examples of congenital cardiovascular defects that are thought to arise from defects in embryonic LR patterning include dextrocardia or mesocardia, levo-transposition of the great arteries and left or right isomerisms. Other commonly associated cardiac defects include pulmonary valvar stenosis, pulmonary atresia, anomalous pulmonary venous return, left superior caval vein, inferior caval vein abnormalities, dextro-TGA, double-outlet right ventricle, ventricular or atrial septal defects, hypoplastic left heart and aortic coarctation.

External references for Position or morphology of thoraco-abdominal organs abnormal

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Genes for phenotype 03.01.09:Position or morphology of thoraco-abdominal organs abnormal

Non-syndromic

ACVR2B

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:9916847 (population study with screening of similar CHD patients and normal controls ) Inheritance: Heterozygous ACVR2B mutations only rarely underlie LR axis malformations with or without complex heart defects. Incidence: rare Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:9916847 Incidence: 3/112 patients Comments: Kosaki et al., 1999 screened for ACVR2B mutations in 112 sporadic and 14 familial cases of LR axis malformations. Two missense substitutions were detected, 1 of which appeared in 2 unrelated individuals. All three patients presented with abdominal situs abnormalities. In addition, one patient presented with dextrocardia, one patient with ventricular inversion (L-TGA) and pulmonic stenosis and the last patient presented with d-TGA, DORV, pulmonic stenosis and AV canal. Add another study.

LEFTY2

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:10053005 (population study with screening of similar CHD patients and normal controls ) Inheritance: LEFTYA mutations underlie a rare cause of L-R malformations with or without heterotaxy-related heart defects. Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:10053005 Incidence: 2/112 patients Comments: Kosaki et al., 1999 screened for LEFTYA or LEFTYB mutations in 112 sporadic and 14 familial cases of L-R axis malformations, and detected one nonsense and one missense mutation in LEFTYA. Both patients presented with d-looping of the ventricles with normally related great arteries, left ventricle hypoplasia, and complete atrioventricular canal defect with a common atrioventricular valve. In addition, they presented with left pulmonary isomerism, left ventricular outflow-tract obstruction, abnormal inferior vena caval drainage and left-sided superior vena cava. Both mutations were inherited from an unaffected parent. However, these mutations were not detected in 200 normal controls. Add another study.

NODAL

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: 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: (1) [ show ] [ hide ] Reference: PMID:19064609 Incidence: 9/269 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. 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: 9 with abnormal situs of the thoracal or abdominal organs (6 of them presented with both thoracal and abdominal situs abnormalities). 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. Add another study.

ZIC3

Support: confirmed: 2 or more independent reports > 1% incidence 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: (2) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 1/145 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:14681828 Incidence: 7/7 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. Add another study.

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Syndromic

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Regions for phenotype 03.01.09:Position or morphology of thoraco-abdominal organs abnormal

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Translocations 03.01.09:Position or morphology of thoraco-abdominal organs abnormal

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Patients reports for 03.01.09:Position or morphology of thoraco-abdominal organs abnormal

Automated text-mining genes found for 03.01.09:Position or morphology of thoraco-abdominal organs abnormal

AGeneApart Method

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This page contributors

• Jeroen Breckpot - CME Leuven (Belgium) (association, study, Free text)

• Sylvain Brohée - Katholieke Universiteit Leuven (Belgium) (Free text)