HPE4
MCID: HLP029
MIFTS: 44

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 56 12 73 29 6 15 71
Hpe4 56 12 73
Holoprosencephaly-4 73 13
Holoprosencephaly, Type 4 39

Characteristics:

OMIM:

56
Inheritance:
autosomal dominant


HPO:

31
holoprosencephaly 4:
Inheritance autosomal dominant inheritance


Classifications:



External Ids:

Disease Ontology 12 DOID:0110880
OMIM 56 142946
OMIM Phenotypic Series 56 PS236100
MeSH 43 D016142
MedGen 41 C1840528
UMLS 71 C1840528

Summaries for Holoprosencephaly 4

UniProtKB/Swiss-Prot : 73 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 central nervous system lipoma and orofaciodigital syndrome viii. An important gene associated with Holoprosencephaly 4 is TGIF1 (TGFB Induced Factor Homeobox 1), and among its related pathways/superpathways are Mesodermal Commitment Pathway and TGF-beta signaling pathway (KEGG). Affiliated tissues include brain, 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.

More information from OMIM: 142946 PS236100

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 49)
# Related Disease Score Top Affiliating Genes
1 central nervous system lipoma 10.2 ZIC2 SIX3
2 orofaciodigital syndrome viii 10.1 ZIC2 SIX3
3 pituitary hypoplasia 10.1 TGIF1 SHH
4 tooth size 10.0 SHH FGF8
5 schizencephaly 10.0 SIX3 SHH
6 colobomatous microphthalmia 10.0 SIX3 SHH
7 choanal atresia, posterior 10.0 SHH FGF8
8 hard palate cancer 10.0 SHH FGF8
9 holoprosencephaly 8 9.9 ZIC2 DISP1 CDON
10 anencephaly 9.9 ZIC2 SIX3 SHH
11 holoprosencephaly, recurrent infections, and monocytosis 9.9 SIX3 GLI2
12 pituitary stalk interruption syndrome 9.8 TGIF1 SHH CDON
13 brachydactyly, type a1 9.8 SHH CDON
14 townes-brocks syndrome 9.8 SHH FGF8
15 holoprosencephaly 1 9.8 ZIC2 SIX3 SHH DISP1
16 nodular medulloblastoma 9.8 SHH GLI2
17 micronodular basal cell carcinoma 9.8 SHH GLI2
18 adult medulloblastoma 9.8 SHH GLI2
19 agnathia-otocephaly complex 9.7 SHH FGF8 CHRD
20 holoprosencephaly 7 9.6 ZIC2 SIX3 FOXH1 DISP1
21 congenital hypopituitarism 9.6 SIX3 SHH GLI2
22 hypopituitarism 9.6 SIX3 SHH GLI2
23 anus, imperforate 9.4 SHH GLI2 FGF8
24 basal cell nevus syndrome 9.4 SHH GLI2 CDON
25 corpus callosum lipoma 9.4 ZIC2 SIX3 SHH GLI2
26 cerebral hemisphere lipoma 9.3 ZIC2 SIX3 SHH GLI2
27 esophageal atresia 9.3 SHH GLI2
28 patau syndrome 9.3 ZIC2 SIX3 SHH FOXH1 DISP1
29 tetralogy of fallot 9.2 SHH FOXH1 FGF8
30 septooptic dysplasia 9.2 SIX3 SHH GLI2 FGF8
31 coloboma of macula 9.2 ZIC2 SIX3 SHH FGF8 CDON
32 microphthalmia 9.1 SIX3 SHH GLI2 CHRD
33 holoprosencephaly 3 9.1 ZIC2 SIX3 SHH GLI2 DISP1
34 greig cephalopolysyndactyly syndrome 9.1 SHH GLI2 FGF8 CDON
35 pallister-hall syndrome 9.0 ZIC2 SIX3 SHH GLI2 FGF8
36 physical disorder 8.9 ZIC2 SIX3 SHH GLI2 FGF8
37 holoprosencephaly 9 8.6 ZIC2 SIX3 GLI2 FOXH1 DISP1 CDON
38 orofacial cleft 8.6 ZIC2 SIX3 SHH GLI2 FGF8 CHRD
39 congenital nervous system abnormality 8.4 ZIC2 TGIF1 SIX3 SHH GLI2 FGF8
40 holoprosencephaly 5 8.3 ZIC2 SIX3 SHH GLI2 FOXH1 DISP1
41 holoprosencephaly 2 8.3 ZIC2 SIX3 SHH GLI2 FOXH1 DISP1
42 holoprosencephaly 11 7.9 ZIC2 SIX3 SHH GLI2 FOXH1 FGF8
43 alobar holoprosencephaly 7.7 ZIC2 TGIF1 SIX3 SHH GLI2 FOXH1
44 lobar holoprosencephaly 7.7 ZIC2 TGIF1 SIX3 SHH GLI2 FOXH1
45 midline interhemispheric variant of holoprosencephaly 7.7 ZIC2 TGIF1 SIX3 SHH GLI2 FOXH1
46 semilobar holoprosencephaly 7.7 ZIC2 TGIF1 SIX3 SHH GLI2 FOXH1
47 septopreoptic holoprosencephaly 7.7 ZIC2 TGIF1 SIX3 SHH GLI2 FOXH1
48 microform holoprosencephaly 7.7 ZIC2 TGIF1 SIX3 SHH GLI2 FOXH1
49 holoprosencephaly 7.0 ZIC2 TGIF2 TGIF1 SIX3 SHH GLI2

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:

31 (show all 8)
# Description HPO Frequency HPO Source Accession
1 ptosis 31 HP:0000508
2 depressed nasal bridge 31 HP:0005280
3 hypotelorism 31 HP:0000601
4 median cleft lip 31 HP:0000161
5 median cleft lip and palate 31 HP:0008501
6 depressed nasal tip 31 HP:0000437
7 absent nasal septal cartilage 31 HP:0005273
8 semilobar holoprosencephaly 31 HP:0002507

Symptoms via clinical synopsis from OMIM:

56
Eyes:
ptosis
hypotelorism

Facies:
flat nasal bridge
flattened nasal tip
absent nasal septum

Neuro:
semilobar holoprosencephaly

Mouth:
wide midline cleft lip/palate

Clinical features from OMIM:

142946

MGI Mouse Phenotypes related to Holoprosencephaly 4:

45 (show all 17)
# Description MGI Source Accession Score Top Affiliating Genes
1 craniofacial MP:0005382 10.29 CDON CHRD DISP1 FGF8 FOXH1 GLI2
2 embryo MP:0005380 10.26 CDON CHRD DISP1 FGF8 FOXH1 GLI2
3 growth/size/body region MP:0005378 10.24 CDON CHRD DISP1 FGF8 FOXH1 GLI2
4 cardiovascular system MP:0005385 10.22 CDON CHRD DISP1 FGF8 FOXH1 SHH
5 cellular MP:0005384 10.21 CDON CHRD DISP1 FGF8 GLI2 SHH
6 digestive/alimentary MP:0005381 10.19 CDON CHRD DISP1 FGF8 FOXH1 GLI2
7 mortality/aging MP:0010768 10.17 CDON CHRD DISP1 FGF8 FOXH1 GLI2
8 nervous system MP:0003631 10.11 CDON CHRD DISP1 FGF8 FOXH1 GLI2
9 endocrine/exocrine gland MP:0005379 10.05 CHRD DISP1 FGF8 FOXH1 GLI2 SHH
10 limbs/digits/tail MP:0005371 10 CDON DISP1 FGF8 GLI2 SHH TGIF1
11 respiratory system MP:0005388 10 CDON CHRD DISP1 FGF8 FOXH1 GLI2
12 normal MP:0002873 9.97 CHRD DISP1 FGF8 FOXH1 GLI2 SHH
13 hearing/vestibular/ear MP:0005377 9.95 CHRD FGF8 FOXH1 GLI2 SHH TGIF1
14 muscle MP:0005369 9.88 CHRD DISP1 FGF8 FOXH1 GLI2 SHH
15 skeleton MP:0005390 9.85 CDON CHRD DISP1 FGF8 FOXH1 GLI2
16 vision/eye MP:0005391 9.36 CDON CHRD DISP1 FGF8 FOXH1 GLI2
17 taste/olfaction MP:0005394 9.35 CHRD SHH SIX3 TGIF1 TGIF2

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:

40
Brain

Publications for Holoprosencephaly 4

Articles related to Holoprosencephaly 4:

(show all 17)
# Title Authors PMID Year
1
Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. 6 56
10835638 2000
2
Physical mapping of the holoprosencephaly critical region in 18p11.3. 61 56
7485158 1995
3
New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. 56
21940735 2011
4
Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. 56
16199538 2006
5
Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. 56
16323008 2006
6
Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations. 6
12522553 2003
7
Holoprosencephaly Overview 6
20301702 2000
8
The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. 56
10556296 1999
9
Segregation analysis in nonsyndromic holoprosencephaly. 56
9605287 1998
10
Molecular detection of a Yp/18 translocation in a 45,X holoprosencephalic male. 56
3192211 1988
11
A 46,XY, del(18)(pter leads to p1 100:) cebocephalic child from a 46,XX,t(12;18)(18pter leads to 18 p 1100:: 12qter leads to 12pter) normal parent. 56
964998 1976
12
Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression. 61
29391420 2018
13
Phenotypic variability in Patau syndrome. 61
24340511 2013
14
Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. 61
22383895 2012
15
Central diabetes insipidus: clinical profile and factors indicating organic etiology in children. 61
18599930 2008
16
Evolutionary conservation, developmental expression, and genomic mapping of mammalian Twisted gastrulation. 61
11420619 2001
17
The human gene ZFP161 on 18p11.21-pter encodes a putative c-myc repressor and is homologous to murine Zfp161 (Chr 17) and Zfp161-rs1 (X Chr) 61
9244432 1997

Variations for Holoprosencephaly 4

ClinVar genetic disease variations for Holoprosencephaly 4:

6 (show all 15) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 TGIF1 NM_003244.3(TGIF1):c.83C>G (p.Ser28Cys)SNV Pathogenic 6979 rs121909066 18:3456418-3456418 18:3456420-3456420
2 TGIF1 NM_003244.3(TGIF1):c.188C>G (p.Pro63Arg)SNV Pathogenic 6980 rs121909067 18:3456523-3456523 18:3456525-3456525
3 TGIF1 NM_003244.3(TGIF1):c.451A>G (p.Thr151Ala)SNV Pathogenic 6981 rs121909068 18:3457570-3457570 18:3457572-3457572
4 TGIF1 NM_003244.3(TGIF1):c.485C>T (p.Ser162Phe)SNV Pathogenic 6982 rs121909069 18:3457604-3457604 18:3457606-3457606
5 TGIF1 NM_003244.3(TGIF1):c.16+1651C>GSNV Pathogenic 6983 rs121909070 18:3452154-3452154 18:3452156-3452156
6 TGIF1 NC_000018.9:g.(?_3447718)_(3457958_?)deldeletion Pathogenic 643155 18:3447718-3457958 18:3447720-3457960
7 TGIF1 NM_173208.2(TGIF1):c.268C>T (p.Arg90Cys)SNV Likely pathogenic 533431 rs1555650923 18:3457387-3457387 18:3457389-3457389
8 TGIF1 NM_173208.2(TGIF1):c.337C>T (p.Arg113Cys)SNV Uncertain significance 545574 rs775078421 18:3457456-3457456 18:3457458-3457458
9 TGIF1 NM_003244.3(TGIF1):c.320A>T (p.Gln107Leu)SNV Likely benign 6984 rs28939693 18:3457439-3457439 18:3457441-3457441
10 TGIF1 NM_003244.3(TGIF1):c.576C>T (p.Val192=)SNV Benign/Likely benign 259018 rs2229335 18:3457695-3457695 18:3457697-3457697
11 TGIF1 NM_003244.3(TGIF1):c.657T>G (p.Thr219=)SNV Benign/Likely benign 259019 rs2229336 18:3457776-3457776 18:3457778-3457778
12 TGIF1 NM_173208.2(TGIF1):c.489G>A (p.Pro163=)SNV Benign/Likely benign 326708 rs2229334 18:3457608-3457608 18:3457610-3457610
13 TGIF1 NM_003244.3(TGIF1):c.16+1845C>TSNV Benign 65496 rs397515501 18:3452348-3452348 18:3452350-3452350
14 TGIF1:c.887C>TSNV Benign 65504
15 TGIF1 NM_003244.3(TGIF1):c.581T>G (p.Val194Gly)SNV Benign 65507 rs397515503 18:3457700-3457700 18:3457702-3457702

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

73
# 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

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 top 50) (show all 53)
# Name GO ID Score Top Affiliating Genes
1 positive regulation of transcription by RNA polymerase II GO:0045944 10.08 SIX3 SHH GLI2 FOXH1 CDON
2 positive regulation of transcription, DNA-templated GO:0045893 10 ZIC2 SHH GLI2 FOXH1
3 negative regulation of transcription by RNA polymerase II GO:0000122 10 TGIF2 TGIF1 SHH GLI2 FOXH1
4 heart development GO:0007507 9.88 SHH GLI2 FGF8
5 central nervous system development GO:0007417 9.8 ZIC2 SHH CHRD
6 kidney development GO:0001822 9.78 SHH GLI2 FGF8
7 positive regulation of neuron differentiation GO:0045666 9.75 TGIF2 GLI2 CDON
8 lung development GO:0030324 9.74 SHH GLI2 FGF8
9 positive regulation of cell differentiation GO:0045597 9.71 SHH FGF8
10 positive regulation of cell division GO:0051781 9.71 SHH FGF8
11 lens development in camera-type eye GO:0002088 9.71 SIX3 CDON
12 branching involved in ureteric bud morphogenesis GO:0001658 9.71 SHH FGF8
13 odontogenesis GO:0042476 9.7 SHH FGF8
14 metanephros development GO:0001656 9.7 SHH FGF8
15 cell fate specification GO:0001708 9.7 SHH CDON
16 pituitary gland development GO:0021983 9.69 SIX3 GLI2
17 developmental growth GO:0048589 9.69 SHH GLI2
18 telencephalon development GO:0021537 9.69 SIX3 FGF8
19 smoothened signaling pathway GO:0007224 9.69 SHH GLI2 CDON
20 embryonic hindlimb morphogenesis GO:0035116 9.68 SHH FGF8
21 branching involved in blood vessel morphogenesis GO:0001569 9.68 SHH FGF8
22 branching morphogenesis of an epithelial tube GO:0048754 9.68 SHH GLI2
23 thyroid gland development GO:0030878 9.67 SHH FGF8
24 positive regulation of mesenchymal cell proliferation GO:0002053 9.67 SHH CHRD
25 dopaminergic neuron differentiation GO:0071542 9.67 SHH FGF8
26 heart looping GO:0001947 9.67 SHH FOXH1 FGF8
27 embryonic pattern specification GO:0009880 9.66 SHH DISP1
28 spinal cord motor neuron differentiation GO:0021522 9.66 SHH GLI2
29 lung morphogenesis GO:0060425 9.65 SHH FGF8
30 embryonic morphogenesis GO:0048598 9.65 SHH CDON
31 hindbrain development GO:0030902 9.65 SHH GLI2
32 striated muscle cell differentiation GO:0051146 9.64 SHH CDON
33 male genitalia development GO:0030539 9.64 SHH FGF8
34 osteoblast development GO:0002076 9.63 SHH GLI2
35 anatomical structure formation involved in morphogenesis GO:0048646 9.63 SHH GLI2
36 pattern specification process GO:0007389 9.63 SHH GLI2 CHRD
37 aorta morphogenesis GO:0035909 9.62 FOXH1 FGF8
38 dorsal/ventral neural tube patterning GO:0021904 9.61 SHH GLI2
39 cell proliferation in forebrain GO:0021846 9.59 SIX3 FGF8
40 branching involved in salivary gland morphogenesis GO:0060445 9.58 SHH FGF8
41 positive regulation of T cell differentiation in thymus GO:0033089 9.56 SHH GLI2
42 anterior/posterior pattern specification GO:0009952 9.56 SHH GLI2 FOXH1 CDON
43 positive regulation of skeletal muscle tissue development GO:0048643 9.55 SHH CDON
44 telencephalon regionalization GO:0021978 9.54 SIX3 SHH
45 anatomical structure development GO:0048856 9.54 SIX3 SHH GLI2
46 forebrain dorsal/ventral pattern formation GO:0021798 9.52 SIX3 FGF8
47 spinal cord dorsal/ventral patterning GO:0021513 9.48 SHH GLI2
48 determination of left/right symmetry GO:0007368 9.46 SHH FOXH1 FGF8 DISP1
49 smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation GO:0021938 9.43 SHH GLI2
50 hindgut morphogenesis GO:0007442 9.4 SHH GLI2

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

# Name GO ID Score Top Affiliating Genes
1 DNA binding GO:0003677 9.73 ZIC2 TGIF2 TGIF1 SIX3 GLI2 FOXH1
2 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.43 ZIC2 TGIF2 TGIF1 SIX3 GLI2 FOXH1
3 co-SMAD binding GO:0070410 9.16 TGIF1 FOXH1
4 DNA-binding transcription factor activity GO:0003700 9.1 ZIC2 TGIF2 TGIF1 SIX3 GLI2 FOXH1

Sources for Holoprosencephaly 4

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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