HPE4
MCID: HLP029
MIFTS: 43

Holoprosencephaly 4 (HPE4)

Categories: Endocrine diseases, Eye 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 72 29 6 15 70
Hpe4 57 12 72
Holoprosencephaly-4 72 13
Holoprosencephaly, Type 4 39

Characteristics:

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal dominant


HPO:

31
holoprosencephaly 4:
Inheritance autosomal dominant inheritance


Classifications:



External Ids:

Disease Ontology 12 DOID:0110880
OMIM® 57 142946
OMIM Phenotypic Series 57 PS236100
MeSH 44 D016142
MedGen 41 C1840528
UMLS 70 C1840528

Summaries for Holoprosencephaly 4

UniProtKB/Swiss-Prot : 72 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 pituitary hypoplasia. 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). 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 42)
# Related Disease Score Top Affiliating Genes
1 central nervous system lipoma 10.2 ZIC2 SIX3
2 pituitary hypoplasia 10.1 TGIF1 SHH
3 schizencephaly 10.1 SIX3 SHH
4 chromosome 18p deletion syndrome 10.1 ZIC2 TGIF1 SIX3
5 orofaciodigital syndrome viii 10.0 ZIC2 SIX3 DISP1
6 hand-foot-genital syndrome 10.0 ZIC2 FGF8
7 tooth size 10.0 SHH FGF8
8 anus, imperforate 10.0 SHH FGF8
9 corpus callosum lipoma 10.0 ZIC2 SIX3 SHH
10 cerebral hemisphere lipoma 10.0 ZIC2 SIX3 SHH
11 sacral defect with anterior meningocele 10.0 SHH FGF8
12 townes-brocks syndrome 9.9 SHH FGF8
13 septooptic dysplasia 9.8 SIX3 SHH FGF8
14 holoprosencephaly 3 9.8 ZIC2 SIX3 SHH DISP1
15 fetal alcohol spectrum disorder 9.8 SHH CDON
16 holoprosencephaly 8 9.7 ZIC2 DISP1 CDON
17 kallmann syndrome 9.7 SIX3 SHH FGF8
18 brachydactyly, type a1 9.7 SHH CDON
19 apert syndrome 9.7 SHH FGF8
20 physical disorder 9.7 ZIC2 SIX3 SHH FGF8
21 agnathia-otocephaly complex 9.7 SHH FGF8 CHRD
22 holoprosencephaly 2 9.5 ZIC2 SIX3 SHH FOXH1 DISP1
23 patau syndrome 9.5 ZIC2 SIX3 SHH FOXH1 DISP1
24 tetralogy of fallot 9.5 SHH FOXH1 FGF8
25 culler-jones syndrome 9.4 ZIC2 TGIF1 SIX3 SHH CDON
26 orofacial cleft 9.3 ZIC2 SIX3 SHH FGF8 CHRD
27 holoprosencephaly 1 9.3 ZIC2 SIX3 SHH FGF8 CDON
28 pallister-hall syndrome 9.2 ZIC2 SIX3 SHH FGF8 CDON
29 coloboma of macula 9.2 ZIC2 SIX3 SHH FGF8 CDON
30 congenital nervous system abnormality 9.1 ZIC2 TGIF1 SIX3 SHH FGF8 CDON
31 holoprosencephaly 9 9.1 ZIC2 SIX3 SHH FOXH1 DISP1 CDON
32 holoprosencephaly 5 9.1 ZIC2 SIX3 SHH FOXH1 DISP1 CDON
33 holoprosencephaly 11 8.8 ZIC2 SIX3 SHH FOXH1 FGF8 DISP1
34 holoprosencephaly 7 8.8 ZIC2 SIX3 SHH FOXH1 FGF8 DISP1
35 alobar holoprosencephaly 8.7 ZIC2 TGIF1 SIX3 SHH FOXH1 FGF8
36 lobar holoprosencephaly 8.6 ZIC2 TGIF1 SIX3 SHH FOXH1 FGF8
37 midline interhemispheric variant of holoprosencephaly 8.6 ZIC2 TGIF1 SIX3 SHH FOXH1 FGF8
38 semilobar holoprosencephaly 8.6 ZIC2 TGIF1 SIX3 SHH FOXH1 FGF8
39 septopreoptic holoprosencephaly 8.6 ZIC2 TGIF1 SIX3 SHH FOXH1 FGF8
40 microform holoprosencephaly 8.6 ZIC2 TGIF1 SIX3 SHH FOXH1 FGF8
41 solitary median maxillary central incisor 8.6 ZIC2 TGIF1 SIX3 SHH FOXH1 FGF8
42 holoprosencephaly 8.1 ZIC2 TGIF2 TGIF1 SIX3 SHH FOXH1

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 depressed nasal tip 31 HP:0000437
6 median cleft lip and palate 31 HP:0008501
7 absent nasal septal cartilage 31 HP:0005273
8 semilobar holoprosencephaly 31 HP:0002507

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
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 (Updated 05-Apr-2021)

MGI Mouse Phenotypes related to Holoprosencephaly 4:

46 (show all 15)
# Description MGI Source Accession Score Top Affiliating Genes
1 cardiovascular system MP:0005385 10.25 CDON CHRD DISP1 FGF8 FOXH1 SHH
2 craniofacial MP:0005382 10.22 CDON CHRD DISP1 FGF8 FOXH1 SHH
3 embryo MP:0005380 10.19 CDON CHRD DISP1 FGF8 FOXH1 SHH
4 growth/size/body region MP:0005378 10.18 CDON CHRD DISP1 FGF8 FOXH1 SHH
5 cellular MP:0005384 10.14 CDON CHRD DISP1 FGF8 SHH TGIF1
6 digestive/alimentary MP:0005381 10.11 CDON CHRD DISP1 FGF8 FOXH1 SHH
7 nervous system MP:0003631 10.11 CDON CHRD DISP1 FGF8 FOXH1 SHH
8 mortality/aging MP:0010768 10.1 CDON CHRD DISP1 FGF8 FOXH1 SHH
9 respiratory system MP:0005388 9.96 CDON CHRD DISP1 FGF8 FOXH1 SHH
10 normal MP:0002873 9.92 CHRD DISP1 FGF8 FOXH1 SHH TGIF1
11 limbs/digits/tail MP:0005371 9.91 CDON DISP1 FGF8 SHH TGIF1 ZIC2
12 hearing/vestibular/ear MP:0005377 9.85 CHRD FGF8 FOXH1 SHH TGIF1
13 skeleton MP:0005390 9.85 CDON CHRD DISP1 FGF8 FOXH1 SHH
14 taste/olfaction MP:0005394 9.35 CHRD SHH SIX3 TGIF1 TGIF2
15 vision/eye MP:0005391 9.32 CDON CHRD DISP1 FGF8 FOXH1 SHH

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

Publications for Holoprosencephaly 4

Articles related to Holoprosencephaly 4:

(show all 21)
# Title Authors PMID Year
1
Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. 6 57
16199538 2006
2
Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. 57 6
10835638 2000
3
Physical mapping of the holoprosencephaly critical region in 18p11.3. 57 61
7485158 1995
4
New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. 57
21940735 2011
5
TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype. 6
22125506 2010
6
Array-CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci. 6
19431187 2009
7
Functional analysis of mutations in TGIF associated with holoprosencephaly. 6
16962354 2007
8
Contiguous gene syndrome of holoprosencephaly and hypotrichosis simplex: association with an 18p11.3 deletion. 6
17001671 2006
9
Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. 57
16323008 2006
10
Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations. 6
12522553 2003
11
Molecular diagnosis of a novel heterozygous 268C-->T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis. 6
11810641 2002
12
The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. 57
10556296 1999
13
Segregation analysis in nonsyndromic holoprosencephaly. 57
9605287 1998
14
Molecular detection of a Yp/18 translocation in a 45,X holoprosencephalic male. 57
3192211 1988
15
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. 57
964998 1976
16
Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression. 61
29391420 2018
17
Phenotypic variability in Patau syndrome. 61
24340511 2013
18
Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. 61
22383895 2012
19
Central diabetes insipidus: clinical profile and factors indicating organic etiology in children. 61
18599930 2008
20
Evolutionary conservation, developmental expression, and genomic mapping of mammalian Twisted gastrulation. 61
11420619 2001
21
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 29)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 TGIF1 NM_003244.3(TGIF1):c.83C>G (p.Ser28Cys) SNV Pathogenic 6979 rs121909066 GRCh37: 18:3456418-3456418
GRCh38: 18:3456420-3456420
2 TGIF1 NM_003244.3(TGIF1):c.188C>G (p.Pro63Arg) SNV Pathogenic 6980 rs121909067 GRCh37: 18:3456523-3456523
GRCh38: 18:3456525-3456525
3 TGIF1 NM_003244.3(TGIF1):c.451A>G (p.Thr151Ala) SNV Pathogenic 6981 rs121909068 GRCh37: 18:3457570-3457570
GRCh38: 18:3457572-3457572
4 TGIF1 NM_003244.3(TGIF1):c.485C>T (p.Ser162Phe) SNV Pathogenic 6982 rs121909069 GRCh37: 18:3457604-3457604
GRCh38: 18:3457606-3457606
5 TGIF1 NM_003244.3(TGIF1):c.16+1651C>G SNV Pathogenic 6983 rs121909070 GRCh37: 18:3452154-3452154
GRCh38: 18:3452156-3452156
6 TGIF1 NC_000018.10:g.(?_3447720)_(3457960_?)del Deletion Pathogenic 643155 GRCh37: 18:3447718-3457958
GRCh38: 18:3447720-3457960
7 TGIF1 NM_003244.3(TGIF1):c.16+1564G>A SNV Pathogenic 252791 rs202123354 GRCh37: 18:3452067-3452067
GRCh38: 18:3452069-3452069
8 TGIF1 NM_003244.4(TGIF1):c.16+1720_16+1721del Deletion Pathogenic 1031713 GRCh37: 18:3452222-3452223
GRCh38: 18:3452224-3452225
9 TGIF1 NM_173208.2(TGIF1):c.268C>T (p.Arg90Cys) SNV Likely pathogenic 533431 rs1555650923 GRCh37: 18:3457387-3457387
GRCh38: 18:3457389-3457389
10 TGIF1 NM_173208.2(TGIF1):c.337C>T (p.Arg113Cys) SNV Uncertain significance 545574 rs775078421 GRCh37: 18:3457456-3457456
GRCh38: 18:3457458-3457458
11 TGIF1 NM_003244.4(TGIF1):c.463C>T (p.Pro155Ser) SNV Uncertain significance 970967 GRCh37: 18:3457582-3457582
GRCh38: 18:3457584-3457584
12 TGIF1 NM_003244.4(TGIF1):c.271C>T (p.Arg91Cys) SNV Uncertain significance 861015 GRCh37: 18:3457390-3457390
GRCh38: 18:3457392-3457392
13 TGIF1 NM_173208.2(TGIF1):c.723G>A (p.Pro241=) SNV Likely benign 326710 rs114912664 GRCh37: 18:3457842-3457842
GRCh38: 18:3457844-3457844
14 TGIF1 NM_173208.2(TGIF1):c.573G>T (p.Ser191=) SNV Likely benign 326709 rs142737563 GRCh37: 18:3457692-3457692
GRCh38: 18:3457694-3457694
15 TGIF1 NM_173208.2(TGIF1):c.*19A>G SNV Likely benign 326711 rs145621092 GRCh37: 18:3457957-3457957
GRCh38: 18:3457959-3457959
16 TGIF1 NM_003244.3(TGIF1):c.657T>G (p.Thr219=) SNV Benign 259019 rs2229336 GRCh37: 18:3457776-3457776
GRCh38: 18:3457778-3457778
17 TGIF1 NM_173208.2(TGIF1):c.489G>A (p.Pro163=) SNV Benign 326708 rs2229334 GRCh37: 18:3457608-3457608
GRCh38: 18:3457610-3457610
18 TGIF1 NM_003244.3(TGIF1):c.576C>T (p.Val192=) SNV Benign 259018 rs2229335 GRCh37: 18:3457695-3457695
GRCh38: 18:3457697-3457697
19 TGIF1 NM_003244.3(TGIF1):c.16+1845C>T SNV Benign 65496 rs397515501 GRCh37: 18:3452348-3452348
GRCh38: 18:3452350-3452350
20 TGIF1 NM_003244.3(TGIF1):c.581T>G (p.Val194Gly) SNV Benign 65507 rs397515503 GRCh37: 18:3457700-3457700
GRCh38: 18:3457702-3457702
21 TGIF1 NM_003244.3(TGIF1):c.123C>T (p.Asn41=) SNV Benign 259014 rs138292737 GRCh37: 18:3456458-3456458
GRCh38: 18:3456460-3456460
22 TGIF1 NM_003244.4(TGIF1):c.60C>T (p.Ser20=) SNV Benign 697792 rs145725785 GRCh37: 18:3456395-3456395
GRCh38: 18:3456397-3456397
23 TGIF1 NM_003244.4(TGIF1):c.228C>A (p.His76Gln) SNV Benign 707438 rs146127624 GRCh37: 18:3456563-3456563
GRCh38: 18:3456565-3456565
24 TGIF1 NM_003244.3(TGIF1):c.488C>T (p.Pro163Leu) SNV Benign 259017 rs2229333 GRCh37: 18:3457607-3457607
GRCh38: 18:3457609-3457609
25 TGIF1 NM_173208.3(TGIF1):c.-462G>A SNV Benign 889042 GRCh37: 18:3449775-3449775
GRCh38: 18:3449777-3449777
26 TGIF1 NM_173208.3(TGIF1):c.-460G>C SNV Benign 889043 GRCh37: 18:3449777-3449777
GRCh38: 18:3449779-3449779
27 TGIF1 NM_173208.3(TGIF1):c.-445G>T SNV Benign 889044 GRCh37: 18:3449792-3449792
GRCh38: 18:3449794-3449794
28 TGIF1 NM_003244.3(TGIF1):c.320A>T (p.Gln107Leu) SNV Benign 6984 rs28939693 GRCh37: 18:3457439-3457439
GRCh38: 18:3457441-3457441
29 TGIF1 NM_003244.3(TGIF1):c.487C>T (p.Pro163Ser) SNV Benign 259016 rs4468717 GRCh37: 18:3457606-3457606
GRCh38: 18:3457608-3457608

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

72
# 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 all 34)
# Name GO ID Score Top Affiliating Genes
1 regulation of transcription, DNA-templated GO:0006355 10.06 TGIF2 TGIF1 SIX3 SHH FOXH1
2 regulation of transcription by RNA polymerase II GO:0006357 10.01 ZIC2 ZBTB14 TGIF2 TGIF1 SIX3 FOXH1
3 negative regulation of transcription by RNA polymerase II GO:0000122 9.89 ZBTB14 TGIF2 TGIF1 SHH FOXH1
4 multicellular organism development GO:0007275 9.73 ZIC2 SIX3 SHH FGF8 DISP1 CHRD
5 kidney development GO:0001822 9.7 ZBTB14 SHH FGF8
6 outflow tract morphogenesis GO:0003151 9.66 FOXH1 FGF8
7 positive regulation of cell division GO:0051781 9.65 SHH FGF8
8 positive regulation of cell differentiation GO:0045597 9.65 SHH FGF8
9 lens development in camera-type eye GO:0002088 9.65 SIX3 CDON
10 anterior/posterior pattern specification GO:0009952 9.65 SHH FOXH1 CDON
11 branching involved in ureteric bud morphogenesis GO:0001658 9.64 SHH FGF8
12 odontogenesis GO:0042476 9.64 SHH FGF8
13 cell fate specification GO:0001708 9.63 SHH CDON
14 metanephros development GO:0001656 9.63 SHH FGF8
15 branching involved in blood vessel morphogenesis GO:0001569 9.62 SHH FGF8
16 embryonic hindlimb morphogenesis GO:0035116 9.62 SHH FGF8
17 telencephalon development GO:0021537 9.61 SIX3 FGF8
18 embryonic pattern specification GO:0009880 9.61 SHH DISP1
19 dopaminergic neuron differentiation GO:0071542 9.6 SHH FGF8
20 thyroid gland development GO:0030878 9.59 SHH FGF8
21 positive regulation of mesenchymal cell proliferation GO:0002053 9.58 SHH CHRD
22 lung morphogenesis GO:0060425 9.58 SHH FGF8
23 embryonic morphogenesis GO:0048598 9.57 SHH CDON
24 striated muscle cell differentiation GO:0051146 9.56 SHH CDON
25 male genitalia development GO:0030539 9.55 SHH FGF8
26 aorta morphogenesis GO:0035909 9.51 FOXH1 FGF8
27 branching involved in salivary gland morphogenesis GO:0060445 9.46 SHH FGF8
28 cell proliferation in forebrain GO:0021846 9.43 SIX3 FGF8
29 positive regulation of skeletal muscle tissue development GO:0048643 9.4 SHH CDON
30 telencephalon regionalization GO:0021978 9.37 SIX3 SHH
31 heart looping GO:0001947 9.33 SHH FOXH1 FGF8
32 forebrain dorsal/ventral pattern formation GO:0021798 9.32 SIX3 FGF8
33 dorsal/ventral pattern formation GO:0009953 9.13 SHH FGF8 DISP1
34 determination of left/right symmetry GO:0007368 8.92 SHH FOXH1 FGF8 DISP1

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

# Name GO ID Score Top Affiliating Genes
1 DNA binding GO:0003677 9.85 ZIC2 ZBTB14 TGIF2 TGIF1 SIX3 FOXH1
2 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.72 ZIC2 TGIF2 TGIF1 SIX3 FOXH1
3 RNA polymerase II proximal promoter sequence-specific DNA binding GO:0000978 9.65 ZIC2 ZBTB14 TGIF2 TGIF1 SIX3
4 sequence-specific double-stranded DNA binding GO:1990837 9.46 ZBTB14 TGIF2 TGIF1 SIX3
5 DNA-binding transcription factor activity GO:0003700 9.02 ZIC2 ZBTB14 TGIF2 TGIF1 FOXH1
6 co-SMAD binding GO:0070410 8.96 TGIF1 FOXH1

Sources for Holoprosencephaly 4

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
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
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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