| Mutation (DNA)
|
Mutation (peptide)
|
CHD
|
Reference
|
Other features
|
Inheritence
|
Additional info.
|
 c.215-221delAGCTGGG
|
Frameshift from amino acid 72 of downstream c
|
ASD
|
PMID:12414819
|
AV block II and atrial fibrillation (VKF), heterotaxy, double orifice mitral valve
|
Dominant Familial
|
 show  hide
| Genetic evidence
|
Segregating in family 5/5 affected members: three family members with suspected heart disease could not be genotyped; 0/81 normal controls
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| in silico prediction
|
5' coding region; frameshift from amino acid 72 of downstream codons causing a truncated protein (172 amino acids) without a homeodomain.
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| Functional studies
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| Comments
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| NM_017617.3:c.262delG
|
NP_060087:p.88A>Xfs
|
ASD
|
PMID:15810002
|
AV block II
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 4/4 affected members (ASD in 1/4), 0/100 normal Japanese controls
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| in silico prediction
|
5' coding region; premature stop codon resulting in truncated nonfunctional protein without the homeodomain and C-terminus
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| Functional studies
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| Comments
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| c.498-499insC
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frameshift and a premature stop codon at amin
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ASD
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PMID:15689439
|
AV block II
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/100 normal controls
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| in silico prediction
|
5' coding region; premature stop codon resulting in truncated nonfunctional protein without the homeodomain and C-terminus
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| Functional studies
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| Comments
|
The c.498-499insC mutation was found in 1 out of 13 sporadic patients with atrial septal defect and/or AV block.
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| c.605-606delGT
|
frameshift and a premature stop codon at amin
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ASD
|
PMID:15689439
|
AV block II and III, VSD
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 3/3 affected members (ASD in 3/3); 0/100 normal controls
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| in silico prediction
|
homeodomain; truncation after the homeodomain results in hypomorphic mutant proteins, with a normal monomeric DNA binding ability, and reduced transcriptional activity (Kasahara H, J Clin Invest 2000)
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| Functional studies
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| Comments
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
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| c.312delG
|
frameshift from amino acid 105 is predicted t
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ASD
|
PMID:16845574
|
AV block I, II and III, VSD, CoAo
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 2/3 affected members (ASD2 2/2; AV block 2/2); DNA of 1 member (with ASD2, VSD, CoAo) not available: 0/100 normal controls
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| in silico prediction
|
3' coding region; frameshift from amino acid 105 is predicted to produce a truncated protein (174 amino acids) without a homeodomain (K104fs70X)
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| Functional studies
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| Comments
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| c.223-224delGT
|
frameshift from amino acid 72 of downstream c
|
ASD
|
PMID:12414819
|
AV block I and II
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 4/5 affected members: 1 member with ASD and AV block could not be genotyped; 0/81 normal controls
|
| in silico prediction
|
5' coding region; frameshift from amino acid 72 of downstream codons causing a truncated protein (105 amino acids) without a homeodomain.
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| Functional studies
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| Comments
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| c.325G>T
|
p.109E>ter
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ASD
|
PMID:17891520
|
AV block, PS, PFO, VSD
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 5/5 affected members (ASD2 5/5; AV block I 4/5; VSD 1/5; PS 1/5; bradycardia 1/5); 0/100 normal controls
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| in silico prediction
|
3' coding region; premature termination codon; stop codon at amino-acid position 109. The truncated protein lacks all of the functionally important domains of the cardiac transcription factor.
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| Functional studies
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| Comments
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| c.380C>A
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p.127A>E
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ASD
|
PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Familial CHD; proband (with ASD2) and grandfather (with BAV) carry mutation; parents asymptomatic; 0/100 normal controls
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| in silico prediction
|
5' coding region; missense nucleotide substitutions
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| Functional studies
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| Comments
|
The c.380C>A mutation was found in 1 out of 71 patients with sporadic ASD. This mutation was inherited from an asymptomatic parent, suggesting variable penetrance.
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| c.554C>T
|
p.149Q>ter
|
ASD
|
PMID:10587520
|
AV block I and II, VSD + ToF, muscular VSD
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 6/6 affected members (ASD 4/6; AV block 5/6; ToF 1/6; muscular VSD 2/6)
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| in silico prediction
|
homeodomain; produce a termination codon in the homeodomain
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| Functional studies
|
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| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
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| c.448G>A
|
p.150V>I
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Multiple VSDs
|
PMID:19933292
|
multiple VSDs
|
Dominant Familial
|
show hide
| Genetic evidence
|
inherited from unaffected father; not detected in 300 normal controls
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| in silico prediction
|
By homology remodelling De Luca et al., 2010 determined that Val 150 is involved in van der Waals contact with residues Phe 145, Gln 147, Leu 153, forming a dense packing of atoms that contributes to the tertiary structure of the DNA binding region of NKX2.5.
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| Functional studies
|
No functional studies available
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| Comments
|
A heterozygous variant was detected in the NKX2.5 gene in one girl with multiple VSDs. 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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|
| c.44A>T
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p.15L>I
|
ASD
|
PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
sporadic patient; inherited from asymptomatic parent; 0/100 normal controls
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| in silico prediction
|
TN domain; missense nucleotide substitutions
|
| Functional studies
|
|
| Comments
|
The c.44A>T mutation was found in 1 out of 71 patients with sporadic ASD. This alteration was inherited from an asymptomatic parent, suggesting variable penetrance.
|
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| c.XXXC>A
|
p.160Q>P
|
ASD
|
PMID:17184575
|
AV block I and II, RBBB
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 4/4 affected members (4/4 ASD2; 3/4 AV block I or II, 1/4 RBBB); 0/100 normal controls
|
| in silico prediction
|
homeodomain; missense mutation; lower affinity or sequence-specificity of target DNA binding
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| Functional studies
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|
| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
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|
| c.512insGC
|
p.170X
|
ASD
|
PMID:20932824
|
Familial ASD with LVNC or AV block
|
Dominant Familial
|
show hide
| Genetic evidence
|
The mutation was found to be inherited from the father, who died suddenly at the age of 29 years. This variant was not identified in 125 sporadic Chinese CHD patients.
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| in silico prediction
|
This variant is predicted to lead to a frame-shift and result in a truncated protein with 175 amino acid residues. Compared with wild type NKX2.5, the mutant NKX2.5 protein lost the second half of α-helix 2 and entire α-helix 3 in the HD domain.
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| Functional studies
|
Wild type and mutant NKX2.5 expression plasmids were transfected into HeLa cells, and immunofluorescence staining with an anti-NKX2.5 antibody was used to characterize cellular localization of NKX2.5. As expected, wild type NKX2.5 is localized into nuclei, however, the mutant NKX2.5 protein generated by the c.512inGC insertion was distributed in both cytoplasm and nuclei. Wild type NKX2.5 can activate the transcription of the ANF promoter by about five fold compared to the empty vector pcDNA3.1, whereas mutant NKX2.5 generated by c.512insGC did not possess any transactivation activity.
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| Comments
|
|
|
| c.533C>T
|
p.178T>M
|
ASD
|
PMID:15810002
|
AV block I and II, SSS (Sick Sinus Syndrome)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Familial CHD; proband and mother carry mutation, no other family members tested
|
| in silico prediction
|
homeodomain; missense mutation; lower affinity or sequence-specificity of target DNA binding
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| Functional studies
|
|
| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
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|
| c.554G>T
|
p.185W>L
|
ASD
|
PMID:15689439
|
(swiss cheese) VSD, LVMN (left ventricle myocardial noncompaction), AV block III
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 3/3 affected members (ASD in 3/3; VSD in 2/3; LVMN in 2/3; AV block in 1/3); 0/100 normal controls
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| in silico prediction
|
homeodomain; missense mutation in conserved region;
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| Functional studies
|
|
| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
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|
| c.673C>A
|
p.188N>K
|
ASD
|
PMID:10587520
|
AV block, Ebstein's anomaly, LV function
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 5/5 affected members (ASD 5/5; AV block 5/5; Ebstein 5/5)
|
| in silico prediction
|
homeodomain; missense mutation in conserved region
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| Functional studies
|
|
| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
|
|
| c.674C>G
|
p.189R>G
|
ASD
|
PMID:10587520
|
AV block, tricuspid abnormalities (small tricuspid valve), LV function
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 5/5 affected members (ASD 4/5; AV block 5/5; tricuspid abnormality 1/5)
|
| in silico prediction
|
homeodomain; missense mutation in conserved region
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| Functional studies
|
|
| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
|
|
| c.568C>T
|
p.190R>C
|
ASD
|
PMID:15810002
|
ASD cribriforme, AV block
|
Dominant Familial
|
show hide
| Genetic evidence
|
Familial CHD; proband carries mutation, no other family members tested; 0/103 normal Japanese controls
|
| in silico prediction
|
homeodomain; missense mutation in conserved region
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| Functional studies
|
|
| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
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|
| c.569G>T
|
p.190R>L
|
ASD
|
PMID:20456451
|
Familial ASD type II
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating : this variant was present in the proband's sister, also suffering from ASD type II. This variant was not detected in 380 normal controls.
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| in silico prediction
|
The predicted missense mutation (p.R190L) is located within the highly conserved homeodomain.
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| Functional studies
|
A mutation altered the coding sense from arginine to histidine at position 190 (p.R190H) was described before in a family with ASD, VSD and AV block. Biochemical analysis of this mutation revealed no DNA binding in electromobility shift assay and a total reduction of transcriptional activation on atrial natriuretic factor (ANF) promoter, which contains multiple NKE sites ([[PMID:15364612|Kasahara H et al., 2004.
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| Comments
|
Further functional studies are required to assess the impact of this variant on cardiac development.
|
|
| c.681A>G
|
p.191Y>C
|
ASD
|
PMID:10587520
|
AV block I, VSD
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo mutation in sporadic patient
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| in silico prediction
|
homeodomain; missense mutation in conserved region
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| Functional studies
|
|
| Comments
|
Missense mutation in the homeodomain results in lower affinity or sequence-specificity of target DNA binding (Schott JJ et al., 1998).
|
|
| c.701C>T
|
p.198Q>ter
|
ASD
|
PMID:10943630
|
AV block, Atrial fibrillation
|
Dominant Familial
|
show hide
| Genetic evidence
|
Familial CHD; proband (with ASD) carries mutation; no DNA available of son with ASD and AV block
|
| in silico prediction
|
3' coding region; nonsense/frameshift mutation; normal binding and transactivation of a ANF-luciferase reporter, but a decreased ability to form dimers.
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| Functional studies
|
normal binding and transactivation of a ANF-luciferase reporter, but a decreased ability to form dimers.
|
| Comments
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
|
|
| c.646C>T
|
p.216R>C
|
Tetralogy of Fallot
|
PMID:11714651
|
Right aortic arch
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
sporadic patient; parental DNA not available; 0/100 normal controls
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| in silico prediction
|
NK2-specific domain; missense nucleotide substitutions.
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| Functional studies
|
Tanaka et al. examined the effects of cardiac-specific deletion of the NK2 domain of NKX2.5 in mice. Null mutants died in utero at E14.5 and exhibited a variety of structural cardiovascular anomalies, including VSD, DORV, and AVSD, as well as downregulation of the ventricular markers Irx4 and MLC-2v, specifically in the right ventricle. Heterozygous NK2 mutant mice, which survived to term, also developed various structural cardiovascular defects. Binding of the NK2 mutant protein to DNA was not impaired, and mutant mice did not demonstrate AV conduction abnormalities. These findings suggest that the NK2 domain plays an important role in cardiovascular development independent of the homeodomain (Tanaka M et al., 2002).
|
| Comments
|
No parental DNA available.
|
|
| c.656C>T
|
p.219A>V
|
Tetralogy of Fallot
|
PMID:11714651
|
Right aortic arch
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
sporadic patient; inherited from asymptomatic parent; 0/100 normal controls
|
| in silico prediction
|
NK2-specific domain; missense nucleotide substitutions
|
| Functional studies
|
Tanaka et al. examined the effects of cardiac-specific deletion of the NK2 domain of NKX2.5 in mice. Null mutants died in utero at E14.5 and exhibited a variety of structural cardiovascular anomalies, including VSD, DORV, and AVSD, as well as downregulation of the ventricular markers Irx4 and MLC-2v, specifically in the right ventricle. Heterozygous NK2 mutant mice, which survived to term, also developed various structural cardiovascular defects. Binding of the NK2 mutant protein to DNA was not impaired, and mutant mice did not demonstrate AV conduction abnormalities. These findings suggest that the NK2 domain plays an important role in cardiovascular development independent of the homeodomain (Tanaka M et al., 2002).
|
| Comments
|
The p.219A>V alteration was inherited from an asymptomatic parent, suggesting variable penetrance.
|
|
| c.61G>C
|
p.21E>Q
|
Tetralogy of Fallot
|
PMID:11714651
|
Retroaortic innominate vein; right aortic arch
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
sporadic patient; inherited from asymptomatic parent; 0/100 normal controls
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions
|
| Functional studies
|
|
| Comments
|
The p.21E>Q alteration was inherited from an asymptomatic parent, suggesting variable penetrance.
|
|
| c.65A>C
|
p.22Q>P
|
Tetralogy of Fallot
|
PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patient (1/67 ToF without del22q11); no parental DNA available; 0/100 normal controls
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions
|
| Functional studies
|
|
| Comments
|
|
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| c.701insTCCCT
|
p.235D>AFSter
|
ASD
|
PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patient; inherited from asymptomatic parent; 0/100 normal controls
|
| in silico prediction
|
3' coding region; five-nucleotide insertion predicted to cause premature termination of translation
|
| Functional studies
|
|
| Comments
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
|
|
| c.762delC
|
p.255A>PfsX38
|
ASD
|
PMID:20456451
|
Familial ASD type II with AV block
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating : this variant was inherited from a mother suffering from ASD II and AV block as well. This variant was not detected in 380 normal controls.
|
| in silico prediction
|
The p.A255PfsX38 variant alters the amino acid sequence of NKX2.5 from amino acids 255 up to 292 and results in a premature termination of translation, leading to the generation of a truncated NKX2.5 protein that carries an intact homeobox and NK2 domain but misses the last 68 amino acids. As the homeodomain of the protein is not altered, one can assume that the phenotype described is not due to a reduced DNA-binding activity. Probably, this mutation changes the affinity of the protein to transcriptional partners and therefore results in dominant-negative effects (Stallmeyer B et al., 2010).
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| Functional studies
|
No functional studies have been performed for this variant yet.
|
| Comments
|
Further functional studies are required to assess the impact of this variant on cardiac development.
|
|
| c.768T>A
|
p.256Y>ter
|
ASD
|
PMID:16896344
|
AV block I, II and atrial fibrillation
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 5/5 affected members (2/5 ASD2, AV block I 2/5, AV block II 2/5, MVP 2/5, RBBB 1/5, LBBB 1/5); 0/110 normal controls
|
| in silico prediction
|
3' coding region; premature termination codon; partially overlaps truncation p.198Q>ter described by Hosoda et al., 1999, probably causing a decreased ability to form dimers
|
| Functional studies
|
Normal binding and transactivation of a ANF-luciferase reporter, but a decreased ability to form dimers Hosoda et al., 1999. The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
|
| Comments
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
|
|
| c.886C>A
|
p.259Y>ter
|
ASD
|
PMID:10587520
|
AV block, VSD + DORV, (perimembranous) VSD, swiss cheese VSD
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 7/7 affected members (ASD 6/7; AV block 7/7; DORV 1/7; muscular VSD 1/7; conotruncal VSD 1/7)
|
| in silico prediction
|
3' coding region; produce a termination codon in the 3' coding region
|
| Functional studies
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
|
| Comments
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
|
|
| c.73C>T
|
p.25R>C
|
Tetralogy of Fallot
|
PMID:11714651
|
Right aortic arch; pulmonary atresia
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patient; no parental DNA available
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions;
|
| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
|
| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
|
|
| c.73C>T
|
p.25R>C
|
Tetralogy of Fallot
|
PMID:11714651
|
Right aortic arch; pulmonary atresia
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 2/2 affected members (proband (with ToF) and father (with VSD))
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions;
|
| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
|
| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
|
|
| c.182C>T
|
p.25R>C
|
Tetralogy of Fallot
|
PMID:10587520
|
VSD
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patient; no parental DNA available
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions;
|
| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
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| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
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| c.73C>T
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p.25R>C
|
Tetralogy of Fallot
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PMID:11714651
|
PFO or secundum ASD (not further specified)
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Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patient; no parental DNA available
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| in silico prediction
|
5' coding region; missense nucleotide substitutions;
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| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
|
| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
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| c.73C>T
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p.25R>C
|
Tetralogy of Fallot
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PMID:19948535
|
right aortic arch; aberrant subclavian artery
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Dominant Sporadic
|
show hide
| Genetic evidence
|
inheritence unknown; not present in 287 normal controls
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| in silico prediction
|
|
| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
|
| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
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| c.73C>T
|
p.25R>C
|
Hypoplastic left heart syndrome
|
PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patients; no parental DNA available
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions;
|
| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
|
| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
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|
| c.73C>T
|
p.25R>C
|
Hypoplastic left heart syndrome
|
PMID:20456451
|
Sporadic HLHS
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Dominant Sporadic
|
show hide
| Genetic evidence
|
This variant was not found in 380 normal controls.
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| in silico prediction
|
5' coding region; missense nucleotide substitutions
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| Functional studies
|
Kasahara H et al., 2004 showed an increase in transcriptional activation in luciferase assay for this sequence alteration.
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| Comments
|
It remains unclear whether this sequence variant is capable to cause the various heart malformations as described. Kasahara H et al., 2004 showed an increase in transcriptional activation in luciferase assay for this sequence alteration and a screening for this nucleotide change in a Caucasian control group (n = 50) was negative. However, it is speculated that it represents rather a polymorphism than a mutation as it also has been observed in 2 of 43 unaffected African Americans and 2 of 185 healthy Turkey individuals, and also not affected family members had been shown to carry this sequence variation (Akcaboy MI et al., 2008).
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| c.73C>T
|
p.25R>C
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Common arterial trunk
|
PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patients; no parental DNA available
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions;
|
| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
|
| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
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| c.73C>T
|
p.25R>C
|
Aortic coarctation
|
PMID:21276881
|
Sporadic aortic coarctation
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Dominant Sporadic
|
show hide
| Genetic evidence
|
Not detected in 200 normal controls.
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| in silico prediction
|
|
| Functional studies
|
Further functional studies are required to assess the impact of this variant on cardiac development. Neither family members nor ethnically matched controls were available to increase the evidence for pathogenicity of these sequence changes.
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| Comments
|
It remains unclear whether this sequence variant is capable to cause the various heart malformations as described. Kasahara H et al., 2004 showed an increase in transcriptional activation in luciferase assay for this sequence alteration and a screening for this nucleotide change in a Caucasian control group (n = 50) was negative. However, it is speculated that it represents rather a polymorphism than a mutation as it also has been observed in 2 of 43 unaffected African Americans and 2 of 185 healthy Turkey individuals, and also not affected family members had been shown to carry this sequence variation (Akcaboy MI et al., 2008).
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| c.73C>T
|
p.25R>C
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Interrupted aortic arch
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PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patients; no parental DNA available
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| in silico prediction
|
5' coding region; missense nucleotide substitutions;
|
| Functional studies
|
Functional analysis of this mutation reported by Kasahara et al. showed normal nuclear localization and normal binding of the mutant protein to monomeric DNA binding sites, but a threefold higher concentration of mutant protein was required for equally distributed binding to monomeric and dimeric DNA binding sites, suggesting a slight impairment of dimerization by the mutant NKX2.5 (Kasahara et al., J Clin Invest, 2000).
|
| Comments
|
The Arg25Cys variant was identified in 2 of 43 (4.7%) black control subjects, although it was identified in 2 of 13 (15.4%) black study subjects (P=0.19). The extent to which this finding in the control population reflects decreased penetrance or this allele predisposes to congenital heart disease is unknown (Goldmuntz et al., 2001).
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| c.901C>A
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p.264C>ter
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ASD
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PMID:12074273
|
AV block I
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Dominant Familial
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show hide
| Genetic evidence
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Segregating Familial CHD; proband (with ASD2 and AV block I) carries mutation; no DNA available of 3 other members with ASD2 and AV block I; no DNA available of 2 other members with AV block
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| in silico prediction
|
3' coding region; truncated protein occurring at the COOH-terminal to the homodomain
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| Functional studies
|
|
| Comments
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
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| c.848C>A
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p.283P>Q
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VSD
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PMID:21110066
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Sporadic VSD, PDA and aortic isthmus stenosis
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Dominant Sporadic
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show hide
| Genetic evidence
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This variant was not detected in 114 healthy control subjects.
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| in silico prediction
|
Kasahara et al., 2000 have suggested that this portion of the gene is critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of the NKX2.5 protein on dimeric DNA binding sites.
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| Functional studies
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No functional studies were performed for this variant.
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| Comments
|
Further functional studies are required to assess the impact of this variant on cardiac development.
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| c.871delAAC
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p.291delN
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Double outlet RV
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PMID:14607454
|
|
Dominant Sporadic
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show hide
| Genetic evidence
|
Sporadic patient (1/31 DORV); inherited from asymptomatic parent; 0/100 normal controls
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| in silico prediction
|
3' coding region; in-frame deletion;
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| Functional studies
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
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| Comments
|
This in-frame deletion was inherited from an asymptomatic parent, suggesting variable penetrance.
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| c.967G>A
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p.323A>T
|
Tetralogy of Fallot
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PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patient (1/67 ToF without del22q11); no parental DNA available; 0/100 normal controls
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| in silico prediction
|
3' coding region; missense nucleotide substitutions;
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| Functional studies
|
|
| Comments
|
The carboxy-terminal portion of NKX2.5 is important in NKX2.5 function distinct from the role of the homeodomain. Kasahara et al. found this portion of the gene to be critical for the cooperative homodimerization and heterodimerization (with other transcription factors such as GATA4) of NKX2.5 protein on dimeric DNA binding sites. In functional studies of the previously reported NKX2.5 mutations, these authors demonstrated decreased binding of mutant NKX2.5 proteins with mutations outside the homeodomain to dimeric DNA binding sites despite normal binding to monomeric sites (Kasahara et al., 2000 and Kasahara et al., 2001).
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| c.188C>T
|
p.63A>V
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Complete transposition of great arteries (IVS)
|
PMID:14607454
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
Sporadic patient; no parental DNA available; 0/100 normal controls
|
| in silico prediction
|
5' coding region; missense nucleotide substitutions
|
| Functional studies
|
|
| Comments
|
|
|
ensembl: ENSG00000183072
OMIM: 600584
Search miRBase for NKX2-5/NKX2.5
Expression patterns from 4DXPress: NKX2-5/NKX2.5
MGI: MGI:97350
ZFIN: ZDB-GENE-980526-321 ZDB-GENE-990415-179
Wikipedia: NKX2-5/NKX2.5
Search Wikiproteins: NKX2-5/NKX2.5
Search Genetic Association Database: NKX2-5/NKX2.5
Search GeneTests: NKX2-5/NKX2.5
CHeartED:
