GDF1

Non syndromic associated CHDs overview

AV and/or VA connections abnormal (1, 8.3%)

Double outlet RV (1, 8.3%)

Complete transposition of great arteries (IVS) (2, 16.7%)

Tetralogy of Fallot (3, 25%)

Right isomerism ('asplenia') (5, 41.7%)

[edit] Synopsis

GDF1 is within the activin-like subclass of TGF-b signaling molecules (activin/Nodal/Vg1). Signal transduction occurs via receptormediated phosphorylation of Smad2 or Smad3, and in the assembly of Smad4 complexes together with cotranscription factors, such as FOXH1, onto target genes (Karkera JD et al., 2007). Absence of Gdf1 in the mouse is associated with disturbances in L-R patterning, including situs inversus, right pulmonary isomerism, TGA, ventricular and atrial defects, and isomerisms (Rankin CT et al., 2000, Wall NA et al., 2000).

External references for GDF1

• ensembl: ENSG00000130283
• OMIM: 602880
• Search miRBase for GDF1
• Expression patterns from 4DXPress: GDF1
• MGI: MGI:95683
• ZFIN:
• Wikipedia: GDF1
• Search Wikiproteins: GDF1
• Search Genetic Association Database: GDF1
• Search GeneTests: GDF1
• CHeartED:

Known phenotypes for GDF1

Non-syndromic

AV and/or VA connections abnormal

Support: unconfirmed: a single case report References: PMID:17924340 (population study with screening of similar CHD patients and normal controls ) Inheritence: 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) [ show ] [ hide ] 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. Add another study.

Complete transposition of great arteries (IVS)

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

Double outlet RV

Support: unconfirmed: a single case report References: PMID:17924340 (population study with screening of similar CHD patients and normal controls ) Inheritence: 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) [ show ] [ hide ] 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. Add another study.

Right isomerism ('asplenia')

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:20413652 (single case report ) Inheritence: Heterotaxy (isomerism or situs inversus) and congenital heart defects are present in patients with (compound) heterozygous GDF1 mutations. Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:20413652 Incidence: 5/5 patients Comments: Kaasinen E et al., 2010 report on a family with autosomal-recessive inheritance of right atrial isomerism. The five affected children were compound heterozygotes for truncating mutations in the growth/differentiation factor 1 (GDF1) gene. Individuals heterozygous for the mutations were clinically healthy. Add another study.

Tetralogy of Fallot

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 ) Inheritence: 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) [ show ] [ hide ] Reference: PMID:17924340 Incidence: 3/375 patients Comments: The patient population was not described for the number of ToFs present. It is therefore not possible to extrapolate what percentage of ToF 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. Add another study.

Add another phenotype.

Syndromic

Add another phenotype.

Protein interaction partners

Patients reports for GDF1

• case 1110 Clinical data Phenotype

Translocations

Add another translocation.

Mutations in GDF1

Mutation (DNA)	Mutation (peptide)	CHD	Reference	Other features	Inheritence	Additional info.
c.681C>A	p.227C>X	Right isomerism ('asplenia')	PMID:20413652	Right atrial isomerism	Recessive Familial	show hide Genetic evidence Segregating the father is a healthy heterozygous carrier; this nonsense mutation was detected in 1/346 normal Finnish controls and 1 out of 271 normal UK controls. in silico prediction c.681C>A is a nonsense mutation in exon 8. The mature protein of GDF1,consisting of residues from 254 to 372, is formed after translation by cleavage. The nonsense mutation resides before the cleavage site, thus preventing the production of the mature protein. Functional studies Gdf1 -/- mice display a complex spectrum of laterality defects in thoracic and abdominal organs (Rankin et al., 2000). These include complex heart malformations, malposition of great arteries, common atrioventricular canal and persistent left vena cava. Gdf1-/- mice also show right pulmonary isomerism, that is, right-sided patterning of lungs on both sides. Further functional studies are required. Comments All five children presented in this study, had a large midline liver, asplenia and bilaterally trilobulated lungs. The cardiac phenotype was characterized by dextrocardia, a common atrium, a univentricular AV connection, malposition of the great arteries, total anomalous pulmonary venous return and pulmonary artery stenosis. In addition to this c.681C>A variant, all affected children harboured a heterozygous GDF1 mutation (c.909insC) on the other allele. All affected children were compound heterozygotes for the two mutations in GDF1, either shown by sequencing or by haplotype analysis from a paraffin-embedded tissue sample (individual II-3), whichwas not of sufficient quality for mutation analysis by sequencing.
c.909insC	p.303fs	Right isomerism ('asplenia')	PMID:20413652	Right atrial isomerism	Recessive Familial	show hide Genetic evidence Segregating the mother is a healthy heterozygous carrier; this nonsense mutation was detected in 2/346 normal Finnish controls. in silico prediction The insertion changes the mature protein product from the residue 303 onwards leading to a severely altered protein and truncation. After the insertion, three out of the six cysteines needed for the disulfide bond formation of the ‘cystine-knot’ structure of GDF1 are lost, and a premature stop codon occurs after 47 residues from the insertion site. Functional studies Gdf1 -/- mice display a complex spectrum of laterality defects in thoracic and abdominal organs (Rankin et al., 2000). These include complex heart malformations, malposition of great arteries, common atrioventricular canal and persistent left vena cava. Gdf1-/- mice also show right pulmonary isomerism, that is, right-sided patterning of lungs on both sides. Further functional studies are required. Comments All five children presented in this study, had a large midline liver, asplenia and bilaterally trilobulated lungs. The cardiac phenotype was characterized by dextrocardia, a common atrium, a univentricular AV connection, malposition of the great arteries, total anomalous pulmonary venous return and pulmonary artery stenosis. In addition to this c.909insC variant, all affected children harboured a heterozygous GDF1 mutation (c.681C>A) on the other allele. All affected children were compound heterozygotes for the two mutations in GDF1, either shown by sequencing or by haplotype analysis from a paraffin-embedded tissue sample (individual II-3), whichwas not of sufficient quality for mutation analysis by sequencing.

Representation of protein GDF1

Heart expression domain of GDF1

No specified expression domain for GDF1

Add a new domain where gene GDF1 is expressed

Associated CHDs found by automated text mining

AGeneApart Method

Huge Navigator (Genopedia)

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Heart defects

This page contributors

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