HPE4
MCID: HLP029
MIFTS: 40

Holoprosencephaly 4 (HPE4)

Categories: Endocrine diseases, Fetal diseases, Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Holoprosencephaly 4

MalaCards integrated aliases for Holoprosencephaly 4:

Name: Holoprosencephaly 4 57 12 75 29 6 15 73
Hpe4 57 12 75
Holoprosencephaly-4 75 13
Holoprosencephaly, Type 4 40

Characteristics:

OMIM:

57
Inheritance:
autosomal dominant


HPO:

32
holoprosencephaly 4:
Inheritance autosomal dominant inheritance


Classifications:



External Ids:

OMIM 57 142946
Disease Ontology 12 DOID:0110880
MedGen 42 C1840528
MeSH 44 D016142
UMLS 73 C1840528

Summaries for Holoprosencephaly 4

UniProtKB/Swiss-Prot : 75 Holoprosencephaly 4: 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.

MalaCards based summary : Holoprosencephaly 4, also known as hpe4, is related to pituitary stalk interruption syndrome and pallister-hall syndrome. An important gene associated with Holoprosencephaly 4 is TGIF1 (TGFB Induced Factor Homeobox 1), and among its related pathways/superpathways are Transcriptional activity of SMAD2/SMAD3-SMAD4 heterotrimer and Ectoderm Differentiation. Affiliated tissues include brain, bone and pituitary, and related phenotypes are ptosis and depressed nasal bridge

Disease Ontology : 12 A holoprosencephaly that has material basis in heterozygous mutation in the TGIF gene on chromosome 18p11.

Description from OMIM: 142946

Related Diseases for Holoprosencephaly 4

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 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 24)
# Related Disease Score Top Affiliating Genes
1 pituitary stalk interruption syndrome 10.1 TGIF1 SHH
2 pallister-hall syndrome 10.1 SHH GLI3
3 greig cephalopolysyndactyly syndrome 10.1 SHH GLI3
4 holoprosencephaly 5 10.0 ZIC2 ZIC1 TGIF1
5 esophageal atresia 10.0 SHH GLI3
6 focal epithelial hyperplasia 10.0 SHH GLI3
7 malignant fibrous histiocytoma of bone 10.0 PTER MYC
8 tracheoesophageal fistula 10.0 SHH GLI3
9 midline interhemispheric variant of holoprosencephaly 10.0 ZIC2 TGIF1 SHH
10 septopreoptic holoprosencephaly 10.0 ZIC2 TGIF1 SHH
11 alobar holoprosencephaly 10.0 ZIC2 TGIF1 SHH
12 lobar holoprosencephaly 10.0 ZIC2 TGIF1 SHH
13 microform holoprosencephaly 10.0 ZIC2 TGIF1 SHH
14 semilobar holoprosencephaly 10.0 SHH TGIF1 ZIC2
15 fibrosarcoma of bone 10.0 PTER MYC
16 basal cell nevus syndrome 9.9 SHH GLI3
17 chromosome 18p deletion syndrome 9.9 PTER SHH ZIC2
18 congenital nervous system abnormality 9.9 PTER SHH ZIC2
19 infratentorial cancer 9.9 GLI3 MYC SHH
20 central nervous system cancer 9.8 SHH MYC
21 brain cancer 9.8 SHH MYC GLI3
22 physical disorder 9.8 ZIC2 SHH PTER GLI3
23 medulloblastoma 9.7 ZIC1 SHH MYC GLI3
24 holoprosencephaly 9.4 ZIC2 ZIC1 TGIF2 TGIF1 SHH GLI3

Graphical network of the top 20 diseases related to Holoprosencephaly 4:



Diseases related to Holoprosencephaly 4

Symptoms & Phenotypes for Holoprosencephaly 4

Symptoms via clinical synopsis from OMIM:

57
Eyes:
ptosis
hypotelorism

Neuro:
semilobar holoprosencephaly

Facies:
flat nasal bridge
flattened nasal tip
absent nasal septum

Mouth:
wide midline cleft lip/palate


Clinical features from OMIM:

142946

Human phenotypes related to Holoprosencephaly 4:

32 (show all 8)
# Description HPO Frequency HPO Source Accession
1 ptosis 32 HP:0000508
2 depressed nasal bridge 32 HP:0005280
3 hypotelorism 32 HP:0000601
4 median cleft lip 32 HP:0000161
5 depressed nasal tip 32 HP:0000437
6 median cleft lip and palate 32 HP:0008501
7 absent nasal septal cartilage 32 HP:0005273
8 semilobar holoprosencephaly 32 HP:0002507

MGI Mouse Phenotypes related to Holoprosencephaly 4:

46 (show all 12)
# Description MGI Source Accession Score Top Affiliating Genes
1 cardiovascular system MP:0005385 10.05 GLI3 MYC SHH TGIF1 TGIF2 ZBTB14
2 growth/size/body region MP:0005378 10 GLI3 MYC SHH TGIF1 TGIF2 ZIC1
3 craniofacial MP:0005382 9.97 GLI3 MYC SHH TGIF1 TGIF2 ZIC2
4 embryo MP:0005380 9.95 GLI3 MYC SHH TGIF1 TGIF2 ZIC2
5 nervous system MP:0003631 9.92 GLI3 MYC SHH TGIF1 TGIF2 ZBTB14
6 mortality/aging MP:0010768 9.91 GLI3 MYC SHH TGIF1 TGIF2 ZIC1
7 limbs/digits/tail MP:0005371 9.8 GLI3 MYC SHH TGIF1 ZIC2
8 hearing/vestibular/ear MP:0005377 9.73 GLI3 MYC SHH TGIF1
9 normal MP:0002873 9.73 GLI3 MYC SHH TGIF1 TGIF2 ZIC2
10 skeleton MP:0005390 9.63 GLI3 MYC SHH TGIF1 ZIC1 ZIC2
11 taste/olfaction MP:0005394 9.26 GLI3 SHH TGIF1 TGIF2
12 vision/eye MP:0005391 9.02 GLI3 SHH TGIF1 TGIF2 ZIC2

Drugs & Therapeutics for Holoprosencephaly 4

Search Clinical Trials , NIH Clinical Center for Holoprosencephaly 4

Genetic Tests for Holoprosencephaly 4

Genetic tests related to Holoprosencephaly 4:

# Genetic test Affiliating Genes
1 Holoprosencephaly 4 29 TGIF1

Anatomical Context for Holoprosencephaly 4

MalaCards organs/tissues related to Holoprosencephaly 4:

41
Brain, Bone, Pituitary

Publications for Holoprosencephaly 4

Variations for Holoprosencephaly 4

UniProtKB/Swiss-Prot genetic disease variations for Holoprosencephaly 4:

75
# Symbol AA change Variation ID SNP ID
1 TGIF1 p.Ser157Cys VAR_009961 rs121909066
2 TGIF1 p.Pro192Arg VAR_009962 rs121909067
3 TGIF1 p.Thr280Ala VAR_009963 rs121909068
4 TGIF1 p.Ser291Phe VAR_009964 rs121909069
5 TGIF1 p.Gln236Leu VAR_023803 rs28939693

ClinVar genetic disease variations for Holoprosencephaly 4:

6 (show all 26)
# Gene Variation Type Significance SNP ID Assembly Location
1 TGIF1 NM_170695.3(TGIF1): c.470C> G (p.Ser157Cys) single nucleotide variant Pathogenic rs121909066 GRCh37 Chromosome 18, 3456418: 3456418
2 TGIF1 NM_170695.3(TGIF1): c.470C> G (p.Ser157Cys) single nucleotide variant Pathogenic rs121909066 GRCh38 Chromosome 18, 3456420: 3456420
3 TGIF1 NM_170695.3(TGIF1): c.575C> G (p.Pro192Arg) single nucleotide variant Pathogenic rs121909067 GRCh37 Chromosome 18, 3456523: 3456523
4 TGIF1 NM_170695.3(TGIF1): c.575C> G (p.Pro192Arg) single nucleotide variant Pathogenic rs121909067 GRCh38 Chromosome 18, 3456525: 3456525
5 TGIF1 NM_170695.3(TGIF1): c.838A> G (p.Thr280Ala) single nucleotide variant Pathogenic rs121909068 GRCh37 Chromosome 18, 3457570: 3457570
6 TGIF1 NM_170695.3(TGIF1): c.838A> G (p.Thr280Ala) single nucleotide variant Pathogenic rs121909068 GRCh38 Chromosome 18, 3457572: 3457572
7 TGIF1 NM_170695.3(TGIF1): c.872C> T (p.Ser291Phe) single nucleotide variant Pathogenic rs121909069 GRCh37 Chromosome 18, 3457604: 3457604
8 TGIF1 NM_170695.3(TGIF1): c.872C> T (p.Ser291Phe) single nucleotide variant Pathogenic rs121909069 GRCh38 Chromosome 18, 3457606: 3457606
9 TGIF1 NM_170695.3(TGIF1): c.177C> G (p.Tyr59Ter) single nucleotide variant Pathogenic rs121909070 GRCh37 Chromosome 18, 3452154: 3452154
10 TGIF1 NM_170695.3(TGIF1): c.177C> G (p.Tyr59Ter) single nucleotide variant Pathogenic rs121909070 GRCh38 Chromosome 18, 3452156: 3452156
11 TGIF1 NM_003244.3(TGIF1): c.320A> T (p.Gln107Leu) single nucleotide variant Likely benign rs28939693 GRCh37 Chromosome 18, 3457439: 3457439
12 TGIF1 NM_003244.3(TGIF1): c.320A> T (p.Gln107Leu) single nucleotide variant Likely benign rs28939693 GRCh38 Chromosome 18, 3457441: 3457441
13 TGIF1 NM_170695.3(TGIF1): c.968T> G (p.Val323Gly) single nucleotide variant Benign rs397515503 GRCh38 Chromosome 18, 3457702: 3457702
14 TGIF1 NM_173208.2(TGIF1): c.489G> A (p.Pro163=) single nucleotide variant Benign/Likely benign rs2229334 GRCh37 Chromosome 18, 3457608: 3457608
15 TGIF1 NM_173208.2(TGIF1): c.489G> A (p.Pro163=) single nucleotide variant Benign/Likely benign rs2229334 GRCh38 Chromosome 18, 3457610: 3457610
16 TGIF1 NM_173208.2(TGIF1): c.268C> T (p.Arg90Cys) single nucleotide variant Likely pathogenic GRCh38 Chromosome 18, 3457389: 3457389
17 TGIF1 NM_173208.2(TGIF1): c.268C> T (p.Arg90Cys) single nucleotide variant Likely pathogenic GRCh37 Chromosome 18, 3457387: 3457387
18 TGIF1 NM_173208.2(TGIF1): c.337C> T (p.Arg113Cys) single nucleotide variant Uncertain significance rs775078421 GRCh37 Chromosome 18, 3457456: 3457456
19 TGIF1 NM_173208.2(TGIF1): c.337C> T (p.Arg113Cys) single nucleotide variant Uncertain significance rs775078421 GRCh38 Chromosome 18, 3457458: 3457458
20 TGIF1 NM_003244.3(TGIF1): c.657T> G (p.Thr219=) single nucleotide variant Benign/Likely benign rs2229336 GRCh38 Chromosome 18, 3457778: 3457778
21 TGIF1 NM_003244.3(TGIF1): c.657T> G (p.Thr219=) single nucleotide variant Benign/Likely benign rs2229336 GRCh37 Chromosome 18, 3457776: 3457776
22 TGIF1 NM_003244.3(TGIF1): c.576C> T (p.Val192=) single nucleotide variant Benign/Likely benign rs2229335 GRCh37 Chromosome 18, 3457695: 3457695
23 TGIF1 NM_003244.3(TGIF1): c.576C> T (p.Val192=) single nucleotide variant Benign/Likely benign rs2229335 GRCh38 Chromosome 18, 3457697: 3457697
24 TGIF1 NM_170695.3(TGIF1): c.371C> T (p.Ala124Val) single nucleotide variant Benign rs397515501 GRCh38 Chromosome 18, 3452350: 3452350
25 TGIF1 NM_170695.3(TGIF1): c.371C> T (p.Ala124Val) single nucleotide variant Benign rs397515501 GRCh37 Chromosome 18, 3452348: 3452348
26 TGIF1 NM_170695.3(TGIF1): c.968T> G (p.Val323Gly) single nucleotide variant Benign rs397515503 GRCh37 Chromosome 18, 3457700: 3457700

Expression for Holoprosencephaly 4

Search GEO for disease gene expression data for Holoprosencephaly 4.

Pathways for Holoprosencephaly 4

GO Terms for Holoprosencephaly 4

Biological processes related to Holoprosencephaly 4 according to GeneCards Suite gene sharing:

(show all 45)
# Name GO ID Score Top Affiliating Genes
1 positive regulation of transcription by RNA polymerase II GO:0045944 9.96 GLI3 MYC SHH ZIC1 ZIC2
2 transcription by RNA polymerase II GO:0006366 9.91 GLI3 MYC ZIC1 ZIC2
3 negative regulation of gene expression GO:0010629 9.83 MYC SHH TGIF1
4 brain development GO:0007420 9.83 GLI3 ZIC1 ZIC2
5 regulation of gene expression GO:0010468 9.81 GLI3 MYC SHH
6 positive regulation of transcription, DNA-templated GO:0045893 9.77 GLI3 MYC SHH ZIC1 ZIC2
7 forebrain development GO:0030900 9.7 GLI3 SHH
8 camera-type eye development GO:0043010 9.69 GLI3 SHH
9 roof of mouth development GO:0060021 9.69 GLI3 SHH
10 smoothened signaling pathway GO:0007224 9.69 GLI3 SHH
11 central nervous system development GO:0007417 9.69 GLI3 SHH ZIC1
12 negative regulation of cell differentiation GO:0045596 9.68 GLI3 SHH
13 embryonic digit morphogenesis GO:0042733 9.68 GLI3 SHH
14 odontogenesis of dentin-containing tooth GO:0042475 9.68 GLI3 SHH
15 embryonic limb morphogenesis GO:0030326 9.68 GLI3 SHH
16 inner ear development GO:0048839 9.67 GLI3 SHH
17 dorsal/ventral pattern formation GO:0009953 9.67 GLI3 SHH
18 limb development GO:0060173 9.67 GLI3 SHH
19 liver regeneration GO:0097421 9.65 GLI3 MYC
20 metanephros development GO:0001656 9.65 GLI3 SHH
21 embryonic organ development GO:0048568 9.64 GLI3 SHH
22 oligodendrocyte differentiation GO:0048709 9.63 GLI3 SHH
23 T cell differentiation in thymus GO:0033077 9.63 GLI3 SHH
24 developmental growth GO:0048589 9.62 GLI3 SHH
25 neuron fate commitment GO:0048663 9.62 GLI3 SHH
26 branching morphogenesis of an epithelial tube GO:0048754 9.61 GLI3 SHH
27 pattern specification process GO:0007389 9.61 GLI3 SHH ZIC1
28 anatomical structure development GO:0048856 9.6 GLI3 SHH
29 positive regulation of mesenchymal cell proliferation GO:0002053 9.59 MYC SHH
30 anatomical structure formation involved in morphogenesis GO:0048646 9.58 GLI3 SHH
31 positive regulation of neuroblast proliferation GO:0002052 9.58 GLI3 SHH
32 spinal cord motor neuron differentiation GO:0021522 9.57 GLI3 SHH
33 embryonic digestive tract morphogenesis GO:0048557 9.55 GLI3 SHH
34 embryonic morphogenesis GO:0048598 9.54 GLI3 SHH
35 prostate gland development GO:0030850 9.52 GLI3 SHH
36 negative thymic T cell selection GO:0045060 9.49 GLI3 SHH
37 positive regulation of alpha-beta T cell differentiation GO:0046638 9.48 GLI3 SHH
38 artery development GO:0060840 9.46 GLI3 SHH
39 spinal cord dorsal/ventral patterning GO:0021513 9.4 GLI3 SHH
40 branching involved in ureteric bud morphogenesis GO:0001658 9.33 GLI3 MYC SHH
41 hindgut morphogenesis GO:0007442 9.32 GLI3 SHH
42 negative regulation of alpha-beta T cell differentiation GO:0046639 9.26 GLI3 SHH
43 positive regulation of protein import into nucleus GO:0042307 9.13 GLI3 SHH ZIC1
44 negative regulation of transcription by RNA polymerase II GO:0000122 9.1 GLI3 MYC SHH TGIF1 TGIF2 ZBTB14
45 regulation of transcription, DNA-templated GO:0006355 10.06 GLI3 MYC SHH TGIF1 TGIF2

Molecular functions related to Holoprosencephaly 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 DNA binding GO:0003677 9.8 GLI3 MYC TGIF1 TGIF2 ZBTB14 ZIC1
2 proximal promoter DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001077 9.62 GLI3 MYC ZIC1 ZIC2
3 RNA polymerase II proximal promoter sequence-specific DNA binding GO:0000978 9.55 GLI3 MYC TGIF1 ZBTB14 ZIC1
4 RNA polymerase II regulatory region sequence-specific DNA binding GO:0000977 9.54 GLI3 ZIC1 ZIC2
5 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.5 GLI3 MYC TGIF1 TGIF2 ZBTB14 ZIC1
6 DNA-binding transcription factor activity GO:0003700 9.17 GLI3 MYC TGIF1 TGIF2 ZBTB14 ZIC1

Sources for Holoprosencephaly 4

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
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