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HPE3
MCID: HLP026
MIFTS: 41

Holoprosencephaly 3 (HPE3)

Categories: Endocrine diseases, Fetal diseases, Genetic diseases, Neuronal diseases, Rare diseases
Genes Variations Tissues Related diseases Publications Pathways Symptoms & Phenotypes
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Aliases & Classifications for Holoprosencephaly 3

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MalaCards integrated aliases for Holoprosencephaly 3:

Name: Holoprosencephaly 3 58 12 76 30 6 15 74
Hpe3 58 12 76
Holoprosencephaly-3 76 13
Hlp3 58 12
Holoprosencephaly, Type 3 41

Characteristics:

OMIM:

58
Inheritance:
autosomal dominant (7q36)


HPO:

33
holoprosencephaly 3:
Onset and clinical course incomplete penetrance
Inheritance autosomal dominant inheritance


Classifications:

MalaCards categories:
Global: Genetic diseases Fetal diseases Rare diseases
Anatomical: Neuronal diseases Endocrine diseases
See all MalaCards categories (disease lists)


External Ids:

Disease Ontology 12 DOID:0110875
OMIM 58 142945
MeSH 45 D016142
MedGen 43 C1840529
UMLS 74 C1840529
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Summaries for Holoprosencephaly 3

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UniProtKB/Swiss-Prot : 76 Holoprosencephaly 3: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described.

MalaCards based summary : Holoprosencephaly 3, also known as hpe3, is related to holoprosencephaly and persian gulf syndrome. An important gene associated with Holoprosencephaly 3 is SHH (Sonic Hedgehog Signaling Molecule), and among its related pathways/superpathways are Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways and G alpha (s) signalling events. Affiliated tissues include brain and eye, and related phenotypes are malar flattening and midface retrusion

Disease Ontology : 12 A holoprosencephaly that has material basis in heterozygous mutation in the SHH gene on chromosome 7q36.

Description from OMIM: 142945
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Related Diseases for Holoprosencephaly 3

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Diseases in the Holoprosencephaly family:

Holoprosencephaly 3 Holoprosencephaly 4
Holoprosencephaly 2 Holoprosencephaly 1
Holoprosencephaly 6 Holoprosencephaly 8
Holoprosencephaly 5 Holoprosencephaly 7
Holoprosencephaly 9 Holoprosencephaly 11
Nonsyndromic Holoprosencephaly

Diseases related to Holoprosencephaly 3 via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 holoprosencephaly 9.8
2 persian gulf syndrome 9.8 ADCYAP1 NPS VIP
3 migraine with or without aura 1 9.6 ADCYAP1 NPS VIP

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Symptoms & Phenotypes for Holoprosencephaly 3

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Human phenotypes related to Holoprosencephaly 3:

33 (show all 8)
# Description HPO Frequency HPO Source Accession
1 malar flattening 33 HP:0000272
2 midface retrusion 33 HP:0011800
3 holoprosencephaly 33 HP:0001360
4 hypotelorism 33 HP:0000601
5 hydronephrosis 33 HP:0000126
6 abnormality of the nose 33 HP:0000366
7 cyclopia 33 HP:0009914
8 proboscis 33 HP:0012806

Symptoms via clinical synopsis from OMIM:

58
Neuro:
holoprosencephaly
single brain ventricle

Eyes:
cyclopia
ocular hypotelorism

G U:
hydronephrosis

Facies:
midface hypoplasia
proboscis

Clinical features from OMIM:

142945

MGI Mouse Phenotypes related to Holoprosencephaly 3:

47
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 9.97 ADCYAP1 EN2 HSPD1 HTR5A KMT2A SHH
2 growth/size/body region MP:0005378 9.96 ADCYAP1 EN2 HLX HSPD1 KMT2A KMT2C
3 liver/biliary system MP:0005370 9.63 ADCYAP1 CYB5A HLX KMT2A RUNX2 SHH
4 no phenotypic analysis MP:0003012 9.43 ADCYAP1 EN2 KMT2A KMT2C RUNX2 SHH
5 reproductive system MP:0005389 9.32 ADCYAP1 EN2 FNDC3A HSPD1 KMT2A KMT2C
Sources

Drugs & Therapeutics for Holoprosencephaly 3

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Search Clinical Trials , NIH Clinical Center for Holoprosencephaly 3

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Genetic Tests for Holoprosencephaly 3

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Genetic tests related to Holoprosencephaly 3:

# Genetic test Affiliating Genes
1 Holoprosencephaly 3 30 SHH
Sources

Anatomical Context for Holoprosencephaly 3

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MalaCards organs/tissues related to Holoprosencephaly 3:

42
Brain, Eye
Sources

Publications for Holoprosencephaly 3

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Articles related to Holoprosencephaly 3:

(show all 11)
# Title Authors Year
1
Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies. ( 20425842 )
2010
2
A sonic hedgehog missense mutation associated with holoprosencephaly causes defective binding to GAS1. ( 19478089 )
2009
3
Mutational analysis of SHH and GLI3 in anorectal malformations. ( 18655123 )
2008
4
Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. ( 16282375 )
2005
5
SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. ( 12709790 )
2003
6
Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability. ( 12567406 )
2003
7
Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. ( 11919111 )
2002
8
The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. ( 10556296 )
1999
9
Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. ( 9302262 )
1997
10
Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. ( 8896572 )
1996
11
Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype. ( 8938447 )
1996
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Variations for Holoprosencephaly 3

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UniProtKB/Swiss-Prot genetic disease variations for Holoprosencephaly 3:

76 (show top 50) (show all 79)
# Symbol AA change Variation ID SNP ID
1 SHH p.Gly31Arg VAR_003619 rs28936675
2 SHH p.Trp117Gly VAR_003620 rs104894040
3 SHH p.Trp117Arg VAR_003621 rs104894040
4 SHH p.Asp88Val VAR_009163 rs104894050
5 SHH p.Gln100His VAR_009164 rs587778792
6 SHH p.Asn115Lys VAR_009165 rs267607047
7 SHH p.Glu188Gln VAR_009166 rs587778799
8 SHH p.Asp222Asn VAR_009167 rs587778805
9 SHH p.Val224Glu VAR_009168 rs104894042
10 SHH p.Ala226Thr VAR_009169 rs104894043
11 SHH p.Ser236Arg VAR_009170 rs587778806
12 SHH p.Gly290Asp VAR_009172 rs104894047
13 SHH p.Ala383Thr VAR_009174 rs137853341
14 SHH p.Pro424Ala VAR_009176 rs104894048
15 SHH p.Ser436Leu VAR_009177
16 SHH p.Arg6Thr VAR_023804
17 SHH p.Ala110Asp VAR_023806
18 SHH p.Thr150Arg VAR_023807
19 SHH p.Leu271Pro VAR_023809
20 SHH p.Val332Ala VAR_023810 rs104894052
21 SHH p.Pro347Gln VAR_023811
22 SHH p.Ile354Thr VAR_023812
23 SHH p.Arg381Pro VAR_023813
24 SHH p.Gly27Ala VAR_039888
25 SHH p.Ile111Asn VAR_039889
26 SHH p.His140Pro VAR_039890
27 SHH p.His140Gln VAR_039891
28 SHH p.Cys183Phe VAR_039892
29 SHH p.Thr267Ile VAR_039893
30 SHH p.Ala373Thr VAR_039894
31 SHH p.Leu17Pro VAR_062592
32 SHH p.Pro26Leu VAR_062593
33 SHH p.Leu39Pro VAR_062594 rs142891682
34 SHH p.Glu53Lys VAR_062595
35 SHH p.Asp83Val VAR_062596
36 SHH p.Ile84Phe VAR_062597
37 SHH p.Cys102Arg VAR_062598
38 SHH p.Cys102Tyr VAR_062599
39 SHH p.Leu109Phe VAR_062600
40 SHH p.Ala110Thr VAR_062601
41 SHH p.Val124Met VAR_062602
42 SHH p.Glu136Lys VAR_062603
43 SHH p.Gly143Asp VAR_062604
44 SHH p.Arg144Pro VAR_062605
45 SHH p.Asp147Asn VAR_062606
46 SHH p.Thr150Lys VAR_062607
47 SHH p.Ser156Arg VAR_062608
48 SHH p.Phe170Cys VAR_062609
49 SHH p.Asp171His VAR_062610
50 SHH p.Cys183Arg VAR_062611

ClinVar genetic disease variations for Holoprosencephaly 3:

6 (show top 50) (show all 91)
# Gene Variation Type Significance SNP ID Assembly Location
1 SHH NM_000193.3(SHH): c.91G> A (p.Gly31Arg) single nucleotide variant Pathogenic rs28936675 GRCh37 Chromosome 7, 155604726: 155604726
2 SHH NM_000193.3(SHH): c.91G> A (p.Gly31Arg) single nucleotide variant Pathogenic rs28936675 GRCh38 Chromosome 7, 155812032: 155812032
3 SHH NM_000193.3(SHH): c.298C> T (p.Gln100Ter) single nucleotide variant Pathogenic rs104894044 GRCh37 Chromosome 7, 155604519: 155604519
4 SHH NM_000193.3(SHH): c.298C> T (p.Gln100Ter) single nucleotide variant Pathogenic rs104894044 GRCh38 Chromosome 7, 155811825: 155811825
5 SHH NM_000193.3(SHH): c.313A> T (p.Lys105Ter) single nucleotide variant Pathogenic rs104894045 GRCh37 Chromosome 7, 155599239: 155599239
6 SHH NM_000193.3(SHH): c.313A> T (p.Lys105Ter) single nucleotide variant Pathogenic rs104894045 GRCh38 Chromosome 7, 155806545: 155806545
7 SHH NM_000193.3(SHH): c.349T> G (p.Trp117Gly) single nucleotide variant Pathogenic rs104894040 GRCh37 Chromosome 7, 155599203: 155599203
8 SHH NM_000193.3(SHH): c.349T> G (p.Trp117Gly) single nucleotide variant Pathogenic rs104894040 GRCh38 Chromosome 7, 155806509: 155806509
9 SHH NM_000193.3(SHH): c.349T> C (p.Trp117Arg) single nucleotide variant Pathogenic rs104894040 GRCh37 Chromosome 7, 155599203: 155599203
10 SHH NM_000193.3(SHH): c.349T> C (p.Trp117Arg) single nucleotide variant Pathogenic rs104894040 GRCh38 Chromosome 7, 155806509: 155806509
11 SHH NM_000193.3(SHH): c.671T> A (p.Val224Glu) single nucleotide variant Pathogenic rs104894042 GRCh37 Chromosome 7, 155596312: 155596312
12 SHH NM_000193.3(SHH): c.671T> A (p.Val224Glu) single nucleotide variant Pathogenic rs104894042 GRCh38 Chromosome 7, 155803618: 155803618
13 SHH NM_000193.3(SHH): c.676G> A (p.Ala226Thr) single nucleotide variant Pathogenic rs104894043 GRCh37 Chromosome 7, 155596307: 155596307
14 SHH NM_000193.3(SHH): c.676G> A (p.Ala226Thr) single nucleotide variant Pathogenic rs104894043 GRCh38 Chromosome 7, 155803613: 155803613
15 SHH NM_000193.3(SHH): c.788_808del21 (p.Arg263_Ala269del) deletion Pathogenic rs397515375 GRCh37 Chromosome 7, 155596175: 155596195
16 SHH NM_000193.3(SHH): c.788_808del21 (p.Arg263_Ala269del) deletion Pathogenic rs397515375 GRCh38 Chromosome 7, 155803481: 155803501
17 SHH NM_000193.3(SHH): c.850G> T (p.Glu284Ter) single nucleotide variant Pathogenic rs104894046 GRCh37 Chromosome 7, 155596133: 155596133
18 SHH NM_000193.3(SHH): c.850G> T (p.Glu284Ter) single nucleotide variant Pathogenic rs104894046 GRCh38 Chromosome 7, 155803439: 155803439
19 SHH NM_000193.3(SHH): c.1147G> A (p.Ala383Thr) single nucleotide variant Uncertain significance rs137853341 GRCh37 Chromosome 7, 155595836: 155595836
20 SHH NM_000193.3(SHH): c.1147G> A (p.Ala383Thr) single nucleotide variant Uncertain significance rs137853341 GRCh38 Chromosome 7, 155803142: 155803142
21 SHH NM_000193.3(SHH): c.869G> A (p.Gly290Asp) single nucleotide variant Conflicting interpretations of pathogenicity rs104894047 GRCh37 Chromosome 7, 155596114: 155596114
22 SHH NM_000193.3(SHH): c.869G> A (p.Gly290Asp) single nucleotide variant Conflicting interpretations of pathogenicity rs104894047 GRCh38 Chromosome 7, 155803420: 155803420
23 SHH NM_000193.3(SHH): c.1270C> G (p.Pro424Ala) single nucleotide variant Pathogenic rs104894048 GRCh37 Chromosome 7, 155595713: 155595713
24 SHH NM_000193.3(SHH): c.1270C> G (p.Pro424Ala) single nucleotide variant Pathogenic rs104894048 GRCh38 Chromosome 7, 155803019: 155803019
25 SHH NM_000193.3(SHH): c.1132_1140del (p.Ala378_Phe380del) deletion Pathogenic rs397515376 GRCh37 Chromosome 7, 155595843: 155595851
26 SHH NM_000193.3(SHH): c.1132_1140del (p.Ala378_Phe380del) deletion Pathogenic rs397515376 GRCh38 Chromosome 7, 155803149: 155803157
27 SHH NM_000193.3(SHH): c.263A> T (p.Asp88Val) single nucleotide variant Pathogenic rs104894050 GRCh37 Chromosome 7, 155604554: 155604554
28 SHH NM_000193.3(SHH): c.263A> T (p.Asp88Val) single nucleotide variant Pathogenic rs104894050 GRCh38 Chromosome 7, 155811860: 155811860
29 SHH NM_000193.3(SHH): c.766G> T (p.Glu256Ter) single nucleotide variant Pathogenic rs104894051 GRCh37 Chromosome 7, 155596217: 155596217
30 SHH NM_000193.3(SHH): c.766G> T (p.Glu256Ter) single nucleotide variant Pathogenic rs104894051 GRCh38 Chromosome 7, 155803523: 155803523
31 SHH NM_000193.2(SHH): c.383G> A (p.Trp128Ter) single nucleotide variant Pathogenic rs104894053 GRCh37 Chromosome 7, 155599169: 155599169
32 SHH NM_000193.2(SHH): c.383G> A (p.Trp128Ter) single nucleotide variant Pathogenic rs104894053 GRCh38 Chromosome 7, 155806475: 155806475
33 SHH NM_000193.3(SHH): c.345C> A (p.Asn115Lys) single nucleotide variant Pathogenic rs267607047 GRCh37 Chromosome 7, 155599207: 155599207
34 SHH NM_000193.3(SHH): c.345C> A (p.Asn115Lys) single nucleotide variant Pathogenic rs267607047 GRCh38 Chromosome 7, 155806513: 155806513
35 SHH NM_000193.3(SHH): c.1005G> A (p.Val335=) single nucleotide variant Benign rs587778774 GRCh37 Chromosome 7, 155595978: 155595978
36 SHH NM_000193.3(SHH): c.1005G> A (p.Val335=) single nucleotide variant Benign rs587778774 GRCh38 Chromosome 7, 155803284: 155803284
37 NM_000193.2: c.1308C> T single nucleotide variant Pathogenic
38 SHH NM_000193.3(SHH): c.1210_1224delGGGGACCGCGGGGGC (p.Asp405_Gly409del) deletion Pathogenic rs587778786 GRCh37 Chromosome 7, 155595759: 155595773
39 SHH NM_000193.3(SHH): c.1210_1224delGGGGACCGCGGGGGC (p.Asp405_Gly409del) deletion Pathogenic rs587778786 GRCh38 Chromosome 7, 155803065: 155803079
40 SHH NM_000193.3(SHH): c.9_10insGCTG (p.Leu4Alafs) insertion Pathogenic rs587778788 GRCh37 Chromosome 7, 155604807: 155604808
41 SHH NM_000193.3(SHH): c.9_10insGCTG (p.Leu4Alafs) insertion Pathogenic rs587778788 GRCh38 Chromosome 7, 155812113: 155812114
42 SHH NM_000193.3(SHH): c.38_45del (p.Val13Alafs) deletion Pathogenic rs587778789 GRCh37 Chromosome 7, 155604772: 155604779
43 SHH NM_000193.3(SHH): c.38_45del (p.Val13Alafs) deletion Pathogenic rs587778789 GRCh38 Chromosome 7, 155812078: 155812085
44 SHH NM_000193.3(SHH): c.300G> C (p.Gln100His) single nucleotide variant Pathogenic rs587778792 GRCh37 Chromosome 7, 155604517: 155604517
45 SHH NM_000193.3(SHH): c.300G> C (p.Gln100His) single nucleotide variant Pathogenic rs587778792 GRCh38 Chromosome 7, 155811823: 155811823
46 SHH NM_000193.3(SHH): c.474C> G (p.Tyr158Ter) single nucleotide variant Pathogenic rs146990376 GRCh37 Chromosome 7, 155599078: 155599078
47 SHH NM_000193.3(SHH): c.474C> G (p.Tyr158Ter) single nucleotide variant Pathogenic rs146990376 GRCh38 Chromosome 7, 155806384: 155806384
48 SHH NM_000193.3(SHH): c.562G> C (p.Glu188Gln) single nucleotide variant Pathogenic rs587778799 GRCh37 Chromosome 7, 155598990: 155598990
49 SHH NM_000193.3(SHH): c.562G> C (p.Glu188Gln) single nucleotide variant Pathogenic rs587778799 GRCh38 Chromosome 7, 155806296: 155806296
50 SHH NM_000193.3(SHH): c.570G> A (p.Ser190=) single nucleotide variant Benign/Likely benign rs9333633 GRCh37 Chromosome 7, 155596413: 155596413
Sources

Expression for Holoprosencephaly 3

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Search GEO for disease gene expression data for Holoprosencephaly 3.
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Pathways for Holoprosencephaly 3

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Pathways related to Holoprosencephaly 3 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways 1
11.67 ADCYAP1 HSPD1 VIPR1 VIPR2
2
G alpha (s) signalling events 67
11.52 ADCYAP1 NPS VIP VIPR1 VIPR2
3
Dopaminergic Neurogenesis 1
10.8 EN2 SHH
4
GPCRs, Class B Secretin-like 1
10.64 VIPR1 VIPR2
5
Microglia Activation During Neuroinflammation: Steady-State Microglia 66
10.58 HSPD1 VIP VIPR1 VIPR2
Sources

GO Terms for Holoprosencephaly 3

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Cellular components related to Holoprosencephaly 3 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 perikaryon GO:0043204 8.8 ADCYAP1 HTR5A VIP

Biological processes related to Holoprosencephaly 3 according to GeneCards Suite gene sharing:

(show all 15)
# Name GO ID Score Top Affiliating Genes
1 G protein-coupled receptor signaling pathway GO:0007186 9.88 ADCYAP1 HTR5A NPS VIP VIPR1 VIPR2
2 positive regulation of transcription by RNA polymerase II GO:0045944 9.8 ADCYAP1 EN2 KMT2A KMT2C RUNX2 SHH
3 midbrain development GO:0030901 9.55 EN2 SHH
4 activation of adenylate cyclase activity GO:0007190 9.54 ADCYAP1 VIPR2
5 embryonic forelimb morphogenesis GO:0035115 9.52 RUNX2 SHH
6 negative regulation of smooth muscle cell proliferation GO:0048662 9.51 VIP VIPR2
7 cAMP-mediated signaling GO:0019933 9.49 ADCYAP1 HTR5A
8 positive regulation of synaptic transmission, glutamatergic GO:0051968 9.48 ADCYAP1 NPS
9 positive regulation of blood vessel diameter GO:0097755 9.46 ADCYAP1 VIP
10 histone H3-K4 methylation GO:0051568 9.43 KMT2A KMT2C
11 hindbrain development GO:0030902 9.37 EN2 SHH
12 osteoblast development GO:0002076 9.26 RUNX2 SHH
13 embryonic digestive tract morphogenesis GO:0048557 9.16 HLX SHH
14 positive regulation of cell proliferation GO:0008284 9.1 ADCYAP1 HLX RUNX2 SHH VIP VIPR1
15 negative regulation of potassium ion transport GO:0043267 8.96 ADCYAP1 VIP

Molecular functions related to Holoprosencephaly 3 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 neuropeptide hormone activity GO:0005184 9.26 ADCYAP1 VIP
2 histone methyltransferase activity (H3-K4 specific) GO:0042800 9.16 KMT2A KMT2C
3 peptide hormone receptor binding GO:0051428 8.96 ADCYAP1 VIP
4 vasoactive intestinal polypeptide receptor activity GO:0004999 8.62 VIPR1 VIPR2
Sources

Sources for Holoprosencephaly 3

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3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
20 FMA
29 GO
30 GTR
31 HGMD
32 HMDB
33 HPO
34 ICD10
35 ICD10 via Orphanet
36 ICD9CM
37 IUPHAR
38 KEGG
39 LifeMap
41 LOVD
43 MedGen
45 MeSH
46 MESH via Orphanet
47 MGI
50 NCI
51 NCIt
52 NDF-RT
55 NINDS
56 Novoseek
58 OMIM
59 OMIM via Orphanet
63 PubMed
65 QIAGEN
70 SNOMED-CT via HPO
71 SNOMED-CT via Orphanet
72 TGDB
73 Tocris
74 UMLS
75 UMLS via Orphanet
The MalaCards human disease database index: 1-9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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