HPE2
MCID: HLP024
MIFTS: 42

Holoprosencephaly 2 (HPE2)

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

Aliases & Classifications for Holoprosencephaly 2

MalaCards integrated aliases for Holoprosencephaly 2:

Name: Holoprosencephaly 2 57 12 74 29 6 15 72
Hpe2 57 12 74
Holoprosencephaly-2 74 13
Holoprosencephaly, Type 2 40

Characteristics:

OMIM:

57
Miscellaneous:
incomplete penetrance
variable severity
genetic heterogeneity
spectrum of malformations resulting from impaired midline cleavage of the embryonic forebrain

Inheritance:
autosomal dominant


HPO:

32
holoprosencephaly 2:
Inheritance autosomal dominant inheritance heterogeneous sporadic
Onset and clinical course variable expressivity incomplete penetrance


Classifications:



External Ids:

Disease Ontology 12 DOID:0110872
MeSH 44 D016142
MedGen 42 C1834877
UMLS 72 C1834877

Summaries for Holoprosencephaly 2

UniProtKB/Swiss-Prot : 74 Holoprosencephaly 2: 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 2, also known as hpe2, is related to deafness, autosomal dominant 10 and schizencephaly, and has symptoms including seizures An important gene associated with Holoprosencephaly 2 is SIX3 (SIX Homeobox 3), and among its related pathways/superpathways is Transcriptional misregulation in cancer. Affiliated tissues include brain, pituitary and bone, and related phenotypes are malar flattening and agenesis of corpus callosum

Disease Ontology : 12 A holoprosencephaly that has material basis in mutation in the homeobox-containing SIX3 gene on chromosome 2p21.

More information from OMIM: 157170 PS236100

Related Diseases for Holoprosencephaly 2

Graphical network of the top 20 diseases related to Holoprosencephaly 2:



Diseases related to Holoprosencephaly 2

Symptoms & Phenotypes for Holoprosencephaly 2

Human phenotypes related to Holoprosencephaly 2:

32 (show all 27)
# Description HPO Frequency HPO Source Accession
1 malar flattening 32 HP:0000272
2 agenesis of corpus callosum 32 HP:0001274
3 intellectual disability 32 HP:0001249
4 seizures 32 HP:0001250
5 muscular hypotonia 32 HP:0001252
6 constipation 32 HP:0002019
7 scoliosis 32 HP:0002650
8 global developmental delay 32 HP:0001263
9 microcephaly 32 HP:0000252
10 generalized hypotonia 32 HP:0001290
11 cerebellar hypoplasia 32 HP:0001321
12 microphthalmia 32 HP:0000568
13 diabetes insipidus 32 HP:0000873
14 holoprosencephaly 32 HP:0001360
15 midface retrusion 32 HP:0011800
16 hypotelorism 32 HP:0000601
17 bifid uvula 32 HP:0000193
18 median cleft lip and palate 32 HP:0008501
19 single median maxillary incisor 32 HP:0006315
20 cyclopia 32 HP:0009914
21 adrenal hypoplasia 32 HP:0000835
22 submucous cleft hard palate 32 HP:0000176
23 absent nasal septal cartilage 32 HP:0005273
24 anterior pituitary agenesis 32 HP:0010626
25 aplasia of the nose 32 HP:0009927
26 single ventricle 32 HP:0001750
27 proboscis 32 HP:0012806

Symptoms via clinical synopsis from OMIM:

57
Neurologic Central Nervous System:
seizures
cerebellar hypoplasia
developmental delay
hypotonia
agenesis of the corpus callosum
more
Head And Neck Eyes:
microphthalmia
cyclopia
ocular hypotelorism
colobomata
varying degrees of doubling of intrinsic ocular structures

Head And Neck Face:
midface hypoplasia
premaxillary agenesis

Head And Neck Mouth:
median cleft lip/palate

Head And Neck Head:
microcephaly

Endocrine Features:
diabetes insipidus
endocrine dysgenesis
pituitary agenesis
hypophyseal agenesis
hypothalamic dysfunction
more
Head And Neck Nose:
arrhinia
blind-ending proboscis
agenesis of nasal bones

Head And Neck Teeth:
central incisor

Clinical features from OMIM:

157170

UMLS symptoms related to Holoprosencephaly 2:


seizures

MGI Mouse Phenotypes related to Holoprosencephaly 2:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 nervous system MP:0003631 9.43 HPGDS NR4A3 SIX1 SIX3 SIX4 SIX6
2 vision/eye MP:0005391 8.92 SIX1 SIX3 SIX4 SIX6

Drugs & Therapeutics for Holoprosencephaly 2

Search Clinical Trials , NIH Clinical Center for Holoprosencephaly 2

Genetic Tests for Holoprosencephaly 2

Genetic tests related to Holoprosencephaly 2:

# Genetic test Affiliating Genes
1 Holoprosencephaly 2 29 SIX3

Anatomical Context for Holoprosencephaly 2

MalaCards organs/tissues related to Holoprosencephaly 2:

41
Brain, Pituitary, Bone, Adrenal Gland, Testes, Olfactory Bulb

Publications for Holoprosencephaly 2

Articles related to Holoprosencephaly 2:

(show all 41)
# Title Authors PMID Year
1
Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. 38 8 71
10369266 1999
2
Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. 8 71
19346217 2009
3
A novel SIX3 mutation segregates with holoprosencephaly in a large family. 8 71
19353631 2009
4
SIX3 mutations with holoprosencephaly. 8 71
17001667 2006
5
Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1. 38 71
15523651 2004
6
A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. 38 71
11039582 2000
7
Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21. 38 8
8824878 1996
8
New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. 8
21940735 2011
9
A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum. 8
21976454 2011
10
The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes. 8
20531442 2010
11
Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly. 71
20157829 2010
12
Mutations in the human SIX3 gene in holoprosencephaly are loss of function. 71
18791198 2008
13
Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. 8
16199538 2006
14
Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. 8
16323008 2006
15
Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations. 8
15221788 2004
16
Holoprosencephaly Overview 71
20301702 2000
17
Segregation analysis in nonsyndromic holoprosencephaly. 8
9605287 1998
18
Forebrain cleavage gene causing holoprosencephaly: deletion mapping to chromosome band 2p21. 8
1887845 1991
19
Agenesis of the nasal septal cartilage: another sign in autosomal dominant holoprosencephaly. 8
1844347 1991
20
Prenatal detection of cyclopia associated with interstitial deletion of 2p. 8
2817010 1989
21
Autosomal dominant inheritance of the DeMyer Sequence. 8
3209682 1988
22
Recurrence of holoprosencephaly in families with a positive history. 8
6652942 1983
23
Dominant inheritance of holoprosencephaly. 8
728563 1978
24
An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly. 8
891015 1977
25
Perinatal mortality in Japanese women diagnosed with gestational diabetes mellitus and diabetes mellitus. 38
28817202 2017
26
Multichannel visual evoked potentials in the assessment of visual pathways in children with marked brain abnormalities. 38
28089743 2017
27
Maturation and Dysgenesis of the Human Olfactory Bulb. 38
26096058 2016
28
Prenatal Diagnosis of Central Nervous System Anomalies by High-Resolution Chromosomal Microarray Analysis. 38
26064910 2015
29
Evaluation and prevalence of major central nervous system malformations: a retrospective study. 38
28058307 2014
30
Pattern of childhood neuronal migrational disorders in Oman. 38
21048602 2009
31
Clinical and neuroimaging profile of congenital brain malformations in children with spastic cerebral palsy. 38
18467267 2008
32
Synthesis and antifungal activity of five classes of diamines. 38
14971680 2004
33
Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children. 38
14671155 2003
34
Effects of a methanolic extract and a hyperforin-enriched CO2 extract of Hypericum perforatum on alcohol intake in rats. 38
11373255 2001
35
Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. 38
10512683 1999
36
Pituitary dysfunction, morbidity and mortality with congenital midline malformation of the cerebrum. 38
10048603 1999
37
Infantile hydrocephalus in southern saudi arabia. 38
23008576 1997
38
Central nervous system malformations in the CHARGE association. 38
2260555 1990
39
Histopathological study of alobar holoprosencephaly. 2. Marginal glioneural heterotopia and other gliomesenchymal abnormalities. 38
2750488 1989
40
[Cerebral ultrasound diagnosis in brain abnormalities]. 38
3796635 1986
41
Mechanism of oxygen transfer by prostaglandin hydroperoxidase. 38
7356613 1980

Variations for Holoprosencephaly 2

ClinVar genetic disease variations for Holoprosencephaly 2:

6 (show all 22)
# Gene Variation Type Significance SNP ID GRCh37 Pos GRCh38 Pos
1 SIX3 NM_005413.4(SIX3): c.441_451del (p.Leu148fs) deletion Pathogenic rs1553337688 2:45169684-45169694 2:44942545-44942555
2 SIX3 NM_005413.4(SIX3): c.676C> G (p.Leu226Val) single nucleotide variant Pathogenic rs121917878 2:45169919-45169919 2:44942780-44942780
3 SIX3 NM_005413.4(SIX3): c.770G> C (p.Arg257Pro) single nucleotide variant Pathogenic rs121917879 2:45170013-45170013 2:44942874-44942874
4 SIX3 NM_005413.4(SIX3): c.749T> C (p.Val250Ala) single nucleotide variant Pathogenic rs121917880 2:45169992-45169992 2:44942853-44942853
5 SIX3 SIX3, 2-BP INS, 557GG insertion Pathogenic
6 SIX3 NM_005413.4(SIX3): c.339G> T (p.Trp113Cys) single nucleotide variant Pathogenic rs137853021 2:45169582-45169582 2:44942443-44942443
7 SIX3 NM_005413.4(SIX3): c.385G> T (p.Glu129Ter) single nucleotide variant Pathogenic rs387906867 2:45169628-45169628 2:44942489-44942489
8 SIX3 NM_005413.4(SIX3): c.696_705del (p.Asn232fs) deletion Pathogenic rs397515502 2:45169939-45169948 2:44942800-44942809
9 SIX3 NM_005413.4(SIX3): c.507G> A (p.Trp169Ter) single nucleotide variant Pathogenic 2:45169750-45169750 2:44942611-44942611
10 SIX3 NM_005413.4(SIX3): c.52A> T (p.Asn18Tyr) single nucleotide variant Uncertain significance 2:45169295-45169295 2:44942156-44942156
11 SIX3 NM_005413.4(SIX3): c.338G> C (p.Trp113Ser) single nucleotide variant Uncertain significance 2:45169581-45169581 2:44942442-44942442
12 SIX3 NM_005413.4(SIX3): c.206G> A (p.Gly69Asp) single nucleotide variant Uncertain significance rs121917881 2:45169449-45169449 2:44942310-44942310
13 SIX3 NM_005413.4(SIX3): c.127G> T (p.Gly43Cys) single nucleotide variant Uncertain significance rs1436891421 2:45169370-45169370 2:44942231-44942231
14 SIX3 NM_005413.4(SIX3): c.887C> G (p.Ser296Trp) single nucleotide variant Uncertain significance rs751280287 2:45171787-45171787 2:44944648-44944648
15 SIX3 NM_005413.4(SIX3): c.169G> T (p.Gly57Cys) single nucleotide variant Uncertain significance rs1344650194 2:45169412-45169412 2:44942273-44942273
16 SIX3 NM_005413.4(SIX3): c.219C> T (p.Pro73=) single nucleotide variant Likely benign rs186163123 2:45169462-45169462 2:44942323-44942323
17 SIX3 NM_005413.4(SIX3): c.525G> A (p.Gln175=) single nucleotide variant Benign/Likely benign rs116680477 2:45169768-45169768 2:44942629-44942629
18 SIX3 NM_005413.4(SIX3): c.109G> T (p.Gly37Cys) single nucleotide variant Benign/Likely benign rs199823175 2:45169352-45169352 2:44942213-44942213
19 SIX3 NM_005413.4(SIX3): c.576C> T (p.Arg192=) single nucleotide variant Benign rs182881 2:45169819-45169819 2:44942680-44942680
20 SIX3 NM_005413.4(SIX3): c.90G> T (p.Ala30=) single nucleotide variant Benign rs78018362 2:45169333-45169333 2:44942194-44942194
21 SIX3: c.942G> A single nucleotide variant Benign
22 SIX3 NM_005413.4(SIX3): c.396_397GC[7] (p.Val137fs) short repeat no interpretation for the single variant rs753473749 2:45169649-45169650 2:44942510-44942511

UniProtKB/Swiss-Prot genetic disease variations for Holoprosencephaly 2:

74 (show all 31)
# Symbol AA change Variation ID SNP ID
1 SIX3 p.Leu226Val VAR_003771 rs121917878
2 SIX3 p.Val250Ala VAR_003772 rs121917880
3 SIX3 p.Arg257Pro VAR_003773 rs121917879
4 SIX3 p.Val92Gly VAR_023797
5 SIX3 p.Ile105Val VAR_023798
6 SIX3 p.His173Pro VAR_023799
7 SIX3 p.Thr202Ile VAR_023800
8 SIX3 p.Pro231Arg VAR_023801
9 SIX3 p.Arg257Trp VAR_023802
10 SIX3 p.Gly69Asp VAR_038418 rs121917881
11 SIX3 p.Met79Val VAR_071336
12 SIX3 p.Ala93Asp VAR_071337
13 SIX3 p.Trp113Cys VAR_071338 rs137853021
14 SIX3 p.Ser114Leu VAR_071339
15 SIX3 p.Val138Asp VAR_071340
16 SIX3 p.Phe157Ile VAR_071342
17 SIX3 p.Ala172Val VAR_071344
18 SIX3 p.Tyr174His VAR_071345
19 SIX3 p.Phe213Val VAR_071346
20 SIX3 p.Arg218Pro VAR_071347
21 SIX3 p.Arg218Trp VAR_071348
22 SIX3 p.Gln227Pro VAR_071349
23 SIX3 p.Gly244Cys VAR_071350 rs989286015
24 SIX3 p.Phe254Leu VAR_071351
25 SIX3 p.Arg257Gly VAR_071352
26 SIX3 p.Arg258Leu VAR_071353
27 SIX3 p.Arg262His VAR_071354
28 SIX3 p.Arg269Met VAR_071355
29 SIX3 p.Arg269Ser VAR_071356
30 SIX3 p.Arg269Thr VAR_071357
31 SIX3 p.Pro297Leu VAR_071358 rs780942050

Expression for Holoprosencephaly 2

Search GEO for disease gene expression data for Holoprosencephaly 2.

Pathways for Holoprosencephaly 2

Pathways related to Holoprosencephaly 2 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 11.07 SIX4 SIX1 NR4A3

GO Terms for Holoprosencephaly 2

Cellular components related to Holoprosencephaly 2 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 transcription factor complex GO:0005667 9.02 SIX6 SIX4 SIX3 SIX1 NR4A3

Biological processes related to Holoprosencephaly 2 according to GeneCards Suite gene sharing:

(show all 31)
# Name GO ID Score Top Affiliating Genes
1 regulation of transcription, DNA-templated GO:0006355 9.99 SIX6 SIX4 SIX3 SIX1 NR4A3
2 multicellular organism development GO:0007275 9.94 SIX6 SIX4 SIX3 SIX1
3 positive regulation of transcription by RNA polymerase II GO:0045944 9.91 SIX6 SIX4 SIX3 SIX1 NR4A3
4 negative regulation of transcription, DNA-templated GO:0045892 9.87 SIX6 SIX4 SIX3 SIX1
5 positive regulation of transcription, DNA-templated GO:0045893 9.83 SIX4 SIX1 NR4A3
6 negative regulation of apoptotic process GO:0043066 9.82 SIX4 SIX1 NR4A3
7 regulation of gene expression GO:0010468 9.77 SIX4 SIX3-AS1 SIX1
8 negative regulation of neuron apoptotic process GO:0043524 9.72 SIX4 SIX1 NR4A3
9 regulation of protein localization GO:0032880 9.64 SIX4 SIX1
10 skeletal muscle tissue development GO:0007519 9.63 SIX4 SIX1
11 embryonic skeletal system morphogenesis GO:0048704 9.63 SIX4 SIX1
12 thymus development GO:0048538 9.62 SIX4 SIX1
13 eye development GO:0001654 9.62 SIX6 SIX3
14 embryonic cranial skeleton morphogenesis GO:0048701 9.61 SIX4 SIX1
15 protein localization to nucleus GO:0034504 9.61 SIX4 SIX1
16 positive regulation of branching involved in ureteric bud morphogenesis GO:0090190 9.58 SIX4 SIX1
17 pharyngeal system development GO:0060037 9.58 SIX4 SIX1
18 inner ear morphogenesis GO:0042472 9.58 SIX4 SIX1 NR4A3
19 regulation of epithelial cell proliferation GO:0050678 9.56 SIX4 SIX1
20 generation of neurons GO:0048699 9.54 SIX4 SIX1
21 tongue development GO:0043586 9.52 SIX4 SIX1
22 myoblast migration GO:0051451 9.49 SIX4 SIX1
23 metanephric mesenchyme development GO:0072075 9.48 SIX4 SIX1
24 trigeminal ganglion development GO:0061551 9.46 SIX4 SIX1
25 regulation of synaptic growth at neuromuscular junction GO:0008582 9.43 SIX4 SIX1
26 positive regulation of ureteric bud formation GO:0072107 9.37 SIX4 SIX1
27 regulation of branch elongation involved in ureteric bud branching GO:0072095 9.32 SIX4 SIX1
28 olfactory placode formation GO:0030910 9.26 SIX4 SIX1
29 myotome development GO:0061055 9.16 SIX4 SIX1
30 fungiform papilla morphogenesis GO:0061197 8.96 SIX4 SIX1
31 anatomical structure development GO:0048856 8.92 SIX6 SIX4 SIX3 SIX1

Molecular functions related to Holoprosencephaly 2 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 DNA binding GO:0003677 9.77 SIX6 SIX4 SIX3 SIX1 NR4A3
2 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.65 SIX6 SIX4 SIX3 SIX1 NR4A3
3 DNA-binding transcription factor activity GO:0003700 9.62 SIX4 SIX3 SIX1 NR4A3
4 RNA polymerase II proximal promoter sequence-specific DNA binding GO:0000978 9.58 SIX4 SIX1 NR4A3
5 sequence-specific DNA binding GO:0043565 9.46 SIX4 SIX3 SIX1 NR4A3
6 transcription coactivator binding GO:0001223 8.96 SIX1 NR4A3
7 transcription regulatory region sequence-specific DNA binding GO:0000976 8.92 SIX6 SIX4 SIX3 SIX1

Sources for Holoprosencephaly 2

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 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 TGDB
71 Tocris
72 UMLS
73 UMLS via Orphanet
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