ZIC3

Non syndromic associated CHDs overview

R aortic arch (1, 2.6%)

Multiple VSDs (1, 2.6%)

Dextrocardia: heart predominantly in R hemithorax (1, 2.6%)

Right isomerism ('asplenia') (1, 2.6%)

VSD (2, 5.1%)

Hypoplastic left heart syndrome (2, 5.1%)

ASD within oval fossa (secundum) (3, 7.7%)

Totally anomalous pulmonary venous connection (3, 7.7%)

Double outlet RV (4, 10.3%)

Pulmonary valvar stenosis - congenital (6, 15.4%)

Complete transposition of great arteries (IVS) (7, 17.9%)

Position or morphology of thoraco-abdominal organs abnormal (8, 20.5%)

[edit] Synopsis

A zinc finger transcription factor encoded on the X chromosome. Mutations in this gene have been found in individuals with X-linked heterotaxy, and sporadically in patients with isolated CHD. The ZIC3 protein plays a role in LR patterning (Purandare et al., 2002) and in cardiac development (Zhu et al., 2007).

External references for ZIC3

• ensembl: ENSG00000156925
• OMIM: 300265
• Search miRBase for ZIC3
• Expression patterns from 4DXPress: ZIC3
• MGI: MGI:106676
• ZFIN: ZDB-GENE-030708-2
• Wikipedia: ZIC3
• Search Wikiproteins: ZIC3
• Search Genetic Association Database: ZIC3
• Search GeneTests: ZIC3
• CHeartED:

Known phenotypes for ZIC3

Non-syndromic

ASD within oval fossa (secundum)

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 ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 1/29 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: 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: 1/1 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.

Complete transposition of great arteries (IVS)

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 ) Inheritence: 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) [ show ] [ hide ] 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. Add another study.

Dextrocardia: heart predominantly in R hemithorax

Support: unconfirmed: a single case report References: PMID:14681828 (population study with screening of similar CHD patients and normal controls ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 1/1 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.

Double outlet RV

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 ) Inheritence: 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) [ show ] [ hide ] 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. Add another study.

Hypoplastic left heart syndrome

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 ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 2/2 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.

Multiple VSDs

Support: unconfirmed: a single case report References: PMID:19933292 (population study with screening of similar CHD patients and normal controls ) Inheritence: X-linked heterotaxy. Single case report of multiple VSDs in a girl who also harboured a mutation in the NKX2.5 gene. Incidence: rare Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:19933292 Incidence: 1/1 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 ZIC3 gene in one girl with multiple VSDs. In addition to this variant, the patient harboured a heterozygous variant in the NKX2.5 gene. Both variants were predicted in silico to be damaging. Add another study.

Position or morphology of thoraco-abdominal organs abnormal

Support: confirmed: 2 or more independent reports > 1% incidence References: PMID:14681828 (population study with screening of similar CHD patients and normal controls ) Inheritence: 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.

Pulmonary valvar stenosis - congenital

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 ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 1/29 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: 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: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. Add another study.

R aortic arch

Support: unconfirmed: a single case report References: PMID:14681828 (population study with screening of similar CHD patients and normal controls ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 1/1 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.

Right isomerism ('asplenia')

Support: unconfirmed: a single case report References: PMID:14681828 (population study with screening of similar CHD patients and normal controls ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 1/1 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.

Totally anomalous pulmonary venous connection

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 ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:14681828 Incidence: 3/3 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.

VSD

Support: unconfirmed: a single case report References: PMID:14681828 (population study with screening of similar CHD patients and normal controls ) Inheritence: 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: 1/1 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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Protein interaction partners

Patients reports for ZIC3

• case 2 Clinical data Phenotype

Translocations

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Mutations in ZIC3

Mutation (DNA)	Mutation (peptide)	CHD	Reference	Other features	Inheritence	Additional info.
	p.17G>C	Complete transposition of great arteries (IVS)	PMID:19933292	non-heterotaxy TGA	Dominant Familial	show hide Genetic evidence inherited from unaffected mother; not detected in 300 normal controls in silico prediction PolyPhen software predicted this variant to be pathogenetic, with a position-specific independent count (PSIC) score difference of 1.9. Functional studies No functional studies available Comments In addition to this variant, the patient harboured a heterozygous variant in the FOXH1 gene (p.21P>S). Both variants were predicted in silico to be damaging. Of note, in addition to the proband, the ZIC3 variant was detected in a family member affected by multiple ventricular septal defects, who also harboured a second sequence variation in the NKX2.5 gene homeodomain (c.448G>A;p.150V>I).
c.1741A>T	p.408K>X	Complete transposition of great arteries (IVS)	PMID:10980576	Non-heterotaxy TGA	X-linked Familial	show hide Genetic evidence Segregating unaffected mother carries the mutation; detected in non-affected uncle; not detected in 200 normal controls in silico prediction This c.1741A>T transversion results in a stop codon, 3 amino acids before the end of the last zinc finger domain, leading to a truncation of the protein. Functional studies No functional studies available. 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.

Representation of protein ZIC3

Heart expression domain of ZIC3

No specified expression domain for ZIC3

Add a new domain where gene ZIC3 is expressed

Associated CHDs found by automated text mining

AGeneApart Method

• Left isomerism ('polysplenia') (03.01.05) (sig = 1.092)

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• Total mirror imagery (atrial situs inversus) (03.01.03) (sig = 0.375)

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Heart defects

This page contributors

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