NOTCH2

Syndromic associated CHDs overview

Tetralogy of Fallot (1, 25%)

Pulmonary valvar stenosis - congenital (1, 25%)

Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation (2, 50%)

[edit] Mutation screens

McDaniell et al., 2006 screened 11 JAG1 mutation-negative probands with Alagille syndrome (AGS) OMIM:118450) for mutations in the NOTCH2 gene and found NOTCH2 mutations segregating in two families. El-Rassy et al., 2007 screened for mutations in the NOTCH2 and Hey2 gene in a AGS family with different clinical phenotypes in three members having one common novel frameshift mutation in JAG1. The screening for mutations in NOTCH2 and Hey2 failed however to reveal any mutation that might account for the discrepancy in the phenotypes.

External references for NOTCH2

• ensembl: ENSG00000134250
• OMIM: 600275
• Search miRBase for NOTCH2
• Expression patterns from 4DXPress: NOTCH2
• MGI: MGI:97364
• ZFIN:
• Wikipedia: NOTCH2
• Search Wikiproteins: NOTCH2
• Search Genetic Association Database: NOTCH2
• Search GeneTests: NOTCH2
• CHeartED:

Known phenotypes for NOTCH2

Non-syndromic

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Syndromic

Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:16773578 (population study with screening of similar CHD patients and normal controls ) Syndromes: Alagille Syndrome (OMIM:118450): neonatal jaundice; eye (posterior embryotoxon and retinal pigmentary changes); heart (pulmonic valvular stenosis, ToF, peripheral arterial stenosis); bones ('butterfly' vertebrae and decrease in interpediculate distance in the lumbar spine); nervous system (absent deep tendon reflexes and poor school performance); facies (broad forehead, pointed mandible and bulbous tip of the nose); fingers (varying degrees of foreshortening) Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:16773578 Incidence: 2/11 patients Comments: McDaniell et al. screened 11 JAG1 mutation-negative probands with Alagille syndrome for alterations in the gene for the Notch2 receptor (NOTCH2)and found NOTCH2 mutations segregating in two families. The first proband presented with peripheral pulmonic stenosis and a small atrial septal defect. The mutation was inherited from an affected mother who presented with valvular and peripheral pulmonic stenosis. The second proband presented with tetralogy of Fallot. Add another study.

Pulmonary valvar stenosis - congenital

Support: unconfirmed: a single case report References: PMID:16773578 (population study with screening of similar CHD patients and normal controls ) Syndromes: Alagille Syndrome (OMIM:118450): neonatal jaundice; eye (posterior embryotoxon and retinal pigmentary changes); heart (pulmonic valvular stenosis, ToF, peripheral arterial stenosis); bones ('butterfly' vertebrae and decrease in interpediculate distance in the lumbar spine); nervous system (absent deep tendon reflexes and poor school performance); facies (broad forehead, pointed mandible and bulbous tip of the nose); fingers (varying degrees of foreshortening) Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:16773578 Incidence: 1/11 patients Comments: McDaniell et al. screened 11 JAG1 mutation-negative probands with Alagille syndrome for alterations in the gene for the Notch2 receptor (NOTCH2)and found NOTCH2 mutations segregating in two families. The first proband presented with peripheral pulmonic stenosis and a small atrial septal defect. The mutation was inherited from an affected mother who presented with valvular and peripheral pulmonic stenosis. The second proband presented with tetralogy of Fallot. Add another study.

Tetralogy of Fallot

Support: unconfirmed: a single case report References: PMID:16773578 (population study with screening of similar CHD patients and normal controls ) Syndromes: Alagille Syndrome (OMIM:118450): neonatal jaundice; eye (posterior embryotoxon and retinal pigmentary changes); heart (pulmonic valvular stenosis, ToF, peripheral arterial stenosis); bones ('butterfly' vertebrae and decrease in interpediculate distance in the lumbar spine); nervous system (absent deep tendon reflexes and poor school performance); facies (broad forehead, pointed mandible and bulbous tip of the nose); fingers (varying degrees of foreshortening) Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:16773578 Incidence: 1/11 patients Comments: McDaniell et al. screened 11 JAG1 mutation-negative probands with Alagille syndrome for alterations in the gene for the Notch2 receptor (NOTCH2)and found NOTCH2 mutations segregating in two families. The first proband presented with peripheral pulmonic stenosis and a small atrial septal defect. The mutation was inherited from an affected mother who presented with valvular and peripheral pulmonic stenosis. The second proband presented with tetralogy of Fallot. Add another study.

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Protein interaction partners

Patients reports for NOTCH2

Translocations

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Mutations in NOTCH2

Mutation (DNA)	Mutation (peptide)	CHD	Reference	Other features	Inheritence	Additional info.
NM_024408.2:c.5930−1Gââ�		Pulmonary valvar stenosis - congenital	PMID:16773578	Family with Alagille syndrome with two affected members in two generations: the proband's mother presented with valvular and peripheral pulmonic stenosis, characteristic facial features, and dysplastic kidneys and proteinuria that resulted in renal failure and a kidney transplant.	Dominant Familial	show hide Genetic evidence Segregating ; de novo change in the proband’s mother; 0/110 ethnically matched control individuals in silico prediction The transcript is predicted to have a premature termination codon within exon 34, and is not predicted to undergo nonsense-mediated mRNA decay. The resulting protein is predicted to lack three of the seven ankyrin repeats and the ensuing 3' sequence. The ankyrin repeat is responsible for mediating protein-protein interactions. These repeats in the intracellular domain of the Notch proteins interact with nuclear cofactors that serve to modulate Notch signaling. Functional studies Comments
c.5930−1G→A		Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation	PMID:16773578	Family with Alagille syndrome with two affected members: the proband presented with cholestatic liver disease, CHD (peripheral pulmonic stenosis and a small atrial septal defect), characteristic facial features, and severe infantile renal disease (small kidneys with cysts bilaterally, renal tubular acidosis, and renal insufficiency); the proband's mother presented with valvular and peripheral pulmonic stenosis, characteristic facial features, and dysplastic kidneys and proteinuria that resulted in renal failure and a kidney transplant.	Dominant Familial	show hide Genetic evidence Segregating de novo change in the proband’s mother; 0/110 ethnically matched control individuals in silico prediction The transcript is predicted to have a premature termination codon within exon 34, and is not predicted to undergo nonsense-mediated mRNA decay. The resulting protein is predicted to lack three of the seven ankyrin repeats and the ensuing 3' sequence. The ankyrin repeat is responsible for mediating protein-protein interactions. These repeats in the intracellular domain of the Notch proteins interact with nuclear cofactors that serve to modulate Notch signaling. Functional studies Comments
NM_024408.2:c.1331G>A	Q04721:p.444C>Y	Tetralogy of Fallot	PMID:16773578	Family with Alagille syndrome with 3 affected members from 3 generations: the proband presented with cholestatic liver disease, tetralogy of Fallot, ocular findings (posterior embryotoxon) and renal disease (tubular acidosis and dysplastic kidneys). Congenital heart defects were not found the affected mother and maternal grandmother.	Dominant Familial	show hide Genetic evidence Segregating 3 affected members from 3 generations; 0/110 ethnically matched control individuals in silico prediction This mutation causes a substitution of a tyrosine for a cysteine residue in the 11th epidermal growth factor (EGF)–like repeat Functional studies Comments

Representation of protein NOTCH2

Heart expression domain of NOTCH2

No specified expression domain for NOTCH2

Add a new domain where gene NOTCH2 is expressed

Associated CHDs found by automated text mining

AGeneApart Method

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Heart defects