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 58 12 76 30 6 15 74
Hpe4 58 12 76
Holoprosencephaly-4 76 13
Holoprosencephaly, Type 4 41

Characteristics:

OMIM:

58
Inheritance:
autosomal dominant


HPO:

33
holoprosencephaly 4:
Inheritance autosomal dominant inheritance


Classifications:



External Ids:

Disease Ontology 12 DOID:0110880
OMIM 58 142946
MeSH 45 D016142
MedGen 43 C1840528
UMLS 74 C1840528

Summaries for Holoprosencephaly 4

UniProtKB/Swiss-Prot : 76 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 chromosome 18p deletion 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 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 23)
# Related Disease Score Top Affiliating Genes
1 pituitary stalk interruption syndrome 10.1 SHH TGIF1
2 chromosome 18p deletion syndrome 10.1 SHH ZIC2
3 pallister-hall syndrome 10.0 GLI3 SHH
4 greig cephalopolysyndactyly syndrome 10.0 GLI3 SHH
5 holoprosencephaly 5 10.0 TGIF1 ZIC1 ZIC2
6 esophageal atresia 10.0 GLI3 SHH
7 focal epithelial hyperplasia 10.0 GLI3 SHH
8 tracheoesophageal fistula 10.0 GLI3 SHH
9 basal cell nevus syndrome 9.9 GLI3 SHH
10 septopreoptic holoprosencephaly 9.9 SHH TGIF1 ZIC2
11 congenital nervous system abnormality 9.9 SHH ZIC2
12 midline interhemispheric variant of holoprosencephaly 9.9 SHH TGIF1 ZIC2
13 alobar holoprosencephaly 9.9 SHH TGIF1 ZIC2
14 lobar holoprosencephaly 9.9 SHH TGIF1 ZIC2
15 microform holoprosencephaly 9.9 SHH TGIF1 ZIC2
16 semilobar holoprosencephaly 9.9 SHH TGIF1 ZIC2
17 physical disorder 9.8 GLI3 SHH ZIC2
18 central nervous system cancer 9.7 MYC SHH
19 infratentorial cancer 9.7 GLI3 MYC SHH
20 nervous system cancer 9.6 MYC SHH
21 brain cancer 9.6 GLI3 MYC SHH
22 medulloblastoma 9.5 GLI3 MYC SHH ZIC1
23 holoprosencephaly 9.1 GLI3 SHH TGIF1 TGIF2 ZIC1 ZIC2

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



Diseases related to Holoprosencephaly 4

Symptoms & Phenotypes for Holoprosencephaly 4

Human phenotypes related to Holoprosencephaly 4:

33 (show all 8)
# Description HPO Frequency HPO Source Accession
1 ptosis 33 HP:0000508
2 depressed nasal bridge 33 HP:0005280
3 hypotelorism 33 HP:0000601
4 median cleft lip 33 HP:0000161
5 depressed nasal tip 33 HP:0000437
6 median cleft lip and palate 33 HP:0008501
7 absent nasal septal cartilage 33 HP:0005273
8 semilobar holoprosencephaly 33 HP:0002507

Symptoms via clinical synopsis from OMIM:

58
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

MGI Mouse Phenotypes related to Holoprosencephaly 4:

47 (show all 14)
# Description MGI Source Accession Score Top Affiliating Genes
1 cardiovascular system MP:0005385 10.08 GLI3 MYC SHH TGIF1 TGIF2 ZBTB14
2 growth/size/body region MP:0005378 10.02 GLI3 MYC SHH TGIF1 TGIF2 ZIC1
3 cellular MP:0005384 10 GLI3 MYC SHH TGIF1 TGIF2 ZIC2
4 craniofacial MP:0005382 9.99 GLI3 MYC SHH TGIF1 TGIF2 ZIC2
5 embryo MP:0005380 9.97 GLI3 MYC SHH TGIF1 TGIF2 ZIC2
6 nervous system MP:0003631 9.97 GLI3 MYC SHH TGIF1 TGIF2 ZBTB14
7 mortality/aging MP:0010768 9.95 GLI3 MYC SHH TGIF1 TGIF2 ZIC1
8 limbs/digits/tail MP:0005371 9.83 GLI3 MYC SHH TGIF1 ZIC2
9 normal MP:0002873 9.8 GLI3 MYC SHH TGIF1 TGIF2 ZIC2
10 hearing/vestibular/ear MP:0005377 9.76 GLI3 MYC SHH TGIF1
11 reproductive system MP:0005389 9.65 GLI3 MYC SHH TGIF1 TGIF2
12 skeleton MP:0005390 9.63 GLI3 MYC SHH TGIF1 ZIC1 ZIC2
13 taste/olfaction MP:0005394 9.26 GLI3 SHH TGIF1 TGIF2
14 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 30 TGIF1

Anatomical Context for Holoprosencephaly 4

MalaCards organs/tissues related to Holoprosencephaly 4:

42
Brain, Pituitary

Publications for Holoprosencephaly 4

Articles related to Holoprosencephaly 4:

# Title Authors Year
1
Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations. ( 12522553 )
2003
2
Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. ( 10835638 )
2000

Variations for Holoprosencephaly 4

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

76
# 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 27)
# 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.371C> T (p.Ala124Val) single nucleotide variant Benign rs397515501 GRCh37 Chromosome 18, 3452348: 3452348
14 TGIF1 NM_170695.3(TGIF1): c.371C> T (p.Ala124Val) single nucleotide variant Benign rs397515501 GRCh38 Chromosome 18, 3452350: 3452350
15 TGIF1: c.887C> T single nucleotide variant Benign
16 TGIF1 NM_170695.3(TGIF1): c.968T> G (p.Val323Gly) single nucleotide variant Benign rs397515503 GRCh37 Chromosome 18, 3457700: 3457700
17 TGIF1 NM_170695.3(TGIF1): c.968T> G (p.Val323Gly) single nucleotide variant Benign rs397515503 GRCh38 Chromosome 18, 3457702: 3457702
18 TGIF1 NM_003244.3(TGIF1): c.576C> T (p.Val192=) single nucleotide variant Benign/Likely benign rs2229335 GRCh38 Chromosome 18, 3457697: 3457697
19 TGIF1 NM_003244.3(TGIF1): c.576C> T (p.Val192=) single nucleotide variant Benign/Likely benign rs2229335 GRCh37 Chromosome 18, 3457695: 3457695
20 TGIF1 NM_003244.3(TGIF1): c.657T> G (p.Thr219=) single nucleotide variant Benign/Likely benign rs2229336 GRCh37 Chromosome 18, 3457776: 3457776
21 TGIF1 NM_003244.3(TGIF1): c.657T> G (p.Thr219=) single nucleotide variant Benign/Likely benign rs2229336 GRCh38 Chromosome 18, 3457778: 3457778
22 TGIF1 NM_173208.2(TGIF1): c.489G> A (p.Pro163=) single nucleotide variant Benign/Likely benign rs2229334 GRCh37 Chromosome 18, 3457608: 3457608
23 TGIF1 NM_173208.2(TGIF1): c.489G> A (p.Pro163=) single nucleotide variant Benign/Likely benign rs2229334 GRCh38 Chromosome 18, 3457610: 3457610
24 TGIF1 NM_173208.2(TGIF1): c.268C> T (p.Arg90Cys) single nucleotide variant Likely pathogenic rs1555650923 GRCh37 Chromosome 18, 3457387: 3457387
25 TGIF1 NM_173208.2(TGIF1): c.268C> T (p.Arg90Cys) single nucleotide variant Likely pathogenic rs1555650923 GRCh38 Chromosome 18, 3457389: 3457389
26 TGIF1 NM_173208.2(TGIF1): c.337C> T (p.Arg113Cys) single nucleotide variant Uncertain significance rs775078421 GRCh37 Chromosome 18, 3457456: 3457456
27 TGIF1 NM_173208.2(TGIF1): c.337C> T (p.Arg113Cys) single nucleotide variant Uncertain significance rs775078421 GRCh38 Chromosome 18, 3457458: 3457458

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 46)
# Name GO ID Score Top Affiliating Genes
1 positive regulation of transcription by RNA polymerase II GO:0045944 9.92 GLI3 MYC SHH ZIC1 ZIC2
2 negative regulation of gene expression GO:0010629 9.83 MYC SHH TGIF1
3 brain development GO:0007420 9.83 GLI3 ZIC1 ZIC2
4 regulation of gene expression GO:0010468 9.8 GLI3 MYC SHH
5 positive regulation of transcription, DNA-templated GO:0045893 9.72 GLI3 MYC SHH ZIC1 ZIC2
6 forebrain development GO:0030900 9.7 GLI3 SHH
7 camera-type eye development GO:0043010 9.69 GLI3 SHH
8 roof of mouth development GO:0060021 9.69 GLI3 SHH
9 smoothened signaling pathway GO:0007224 9.69 GLI3 SHH
10 central nervous system development GO:0007417 9.69 GLI3 SHH ZIC1
11 negative regulation of cell differentiation GO:0045596 9.68 GLI3 SHH
12 embryonic digit morphogenesis GO:0042733 9.68 GLI3 SHH
13 odontogenesis of dentin-containing tooth GO:0042475 9.68 GLI3 SHH
14 embryonic limb morphogenesis GO:0030326 9.68 GLI3 SHH
15 inner ear development GO:0048839 9.67 GLI3 SHH
16 dorsal/ventral pattern formation GO:0009953 9.67 GLI3 SHH
17 limb development GO:0060173 9.67 GLI3 SHH
18 liver regeneration GO:0097421 9.66 GLI3 MYC
19 metanephros development GO:0001656 9.65 GLI3 SHH
20 embryonic organ development GO:0048568 9.65 GLI3 SHH
21 oligodendrocyte differentiation GO:0048709 9.64 GLI3 SHH
22 T cell differentiation in thymus GO:0033077 9.63 GLI3 SHH
23 developmental growth GO:0048589 9.62 GLI3 SHH
24 neuron fate commitment GO:0048663 9.62 GLI3 SHH
25 branching morphogenesis of an epithelial tube GO:0048754 9.61 GLI3 SHH
26 anatomical structure development GO:0048856 9.61 GLI3 SHH
27 positive regulation of mesenchymal cell proliferation GO:0002053 9.6 MYC SHH
28 anatomical structure formation involved in morphogenesis GO:0048646 9.58 GLI3 SHH
29 positive regulation of neuroblast proliferation GO:0002052 9.58 GLI3 SHH
30 pattern specification process GO:0007389 9.58 GLI3 SHH ZIC1
31 spinal cord motor neuron differentiation GO:0021522 9.57 GLI3 SHH
32 embryonic digestive tract morphogenesis GO:0048557 9.56 GLI3 SHH
33 embryonic morphogenesis GO:0048598 9.55 GLI3 SHH
34 prostate gland development GO:0030850 9.54 GLI3 SHH
35 negative thymic T cell selection GO:0045060 9.49 GLI3 SHH
36 positive regulation of alpha-beta T cell differentiation GO:0046638 9.48 GLI3 SHH
37 artery development GO:0060840 9.46 GLI3 SHH
38 spinal cord dorsal/ventral patterning GO:0021513 9.43 GLI3 SHH
39 hindgut morphogenesis GO:0007442 9.37 GLI3 SHH
40 branching involved in ureteric bud morphogenesis GO:0001658 9.33 GLI3 MYC SHH
41 transcription by RNA polymerase II GO:0006366 9.29 MYC
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 10.04 GLI3 MYC SHH TGIF1 TGIF2
46 multicellular organism development GO:0007275 10 SHH TGIF1 ZIC1 ZIC2

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 nucleic acid binding GO:0003676 9.67 GLI3 ZBTB14 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 9.5 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 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
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