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 58 12 76 30 6 15 74
Hpe2 58 12 76
Holoprosencephaly-2 76 13
Holoprosencephaly, Type 2 41

Characteristics:

OMIM:

58
Inheritance:
autosomal dominant

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


HPO:

33
holoprosencephaly 2:
Onset and clinical course variable expressivity incomplete penetrance
Inheritance heterogeneous autosomal dominant inheritance sporadic


Classifications:



Summaries for Holoprosencephaly 2

UniProtKB/Swiss-Prot : 76 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.

Description from OMIM: 157170

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:

33 (show all 27)
# Description HPO Frequency HPO Source Accession
1 malar flattening 33 HP:0000272
2 agenesis of corpus callosum 33 HP:0001274
3 intellectual disability 33 HP:0001249
4 seizures 33 HP:0001250
5 muscular hypotonia 33 HP:0001252
6 constipation 33 HP:0002019
7 scoliosis 33 HP:0002650
8 global developmental delay 33 HP:0001263
9 microcephaly 33 HP:0000252
10 cerebellar hypoplasia 33 HP:0001321
11 microphthalmia 33 HP:0000568
12 diabetes insipidus 33 HP:0000873
13 midface retrusion 33 HP:0011800
14 holoprosencephaly 33 HP:0001360
15 hypotelorism 33 HP:0000601
16 bifid uvula 33 HP:0000193
17 generalized hypotonia 33 HP:0001290
18 single median maxillary incisor 33 HP:0006315
19 median cleft lip and palate 33 HP:0008501
20 cyclopia 33 HP:0009914
21 adrenal hypoplasia 33 HP:0000835
22 submucous cleft hard palate 33 HP:0000176
23 absent nasal septal cartilage 33 HP:0005273
24 anterior pituitary agenesis 33 HP:0010626
25 aplasia of the nose 33 HP:0009927
26 proboscis 33 HP:0012806
27 single ventricle 33 HP:0001750

Symptoms via clinical synopsis from OMIM:

58
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:

47
# 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 30 SIX3

Anatomical Context for Holoprosencephaly 2

MalaCards organs/tissues related to Holoprosencephaly 2:

42
Brain, Pituitary, Bone, Adrenal Gland

Publications for Holoprosencephaly 2

Articles related to Holoprosencephaly 2:

# Title Authors Year
1
Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly. ( 20157829 )
2010
2
Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. ( 19346217 )
2009
3
A novel SIX3 mutation segregates with holoprosencephaly in a large family. ( 19353631 )
2009
4
Mutations in the human SIX3 gene in holoprosencephaly are loss of function. ( 18791198 )
2008
5
SIX3 mutations with holoprosencephaly. ( 17001667 )
2006
6
Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1. ( 15523651 )
2004
7
A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. ( 11039582 )
2000
8
Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. ( 10369266 )
1999
9
Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21. ( 8824878 )
1996
10
Histopathological study of alobar holoprosencephaly. 2. Marginal glioneural heterotopia and other gliomesenchymal abnormalities. ( 2750488 )
1989

Variations for Holoprosencephaly 2

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

76 (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

ClinVar genetic disease variations for Holoprosencephaly 2:

6 (show all 40)
# Gene Variation Type Significance SNP ID Assembly Location
1 SIX3 NM_005413.3(SIX3): c.676C> G (p.Leu226Val) single nucleotide variant Pathogenic rs121917878 GRCh37 Chromosome 2, 45169919: 45169919
2 SIX3 NM_005413.3(SIX3): c.676C> G (p.Leu226Val) single nucleotide variant Pathogenic rs121917878 GRCh38 Chromosome 2, 44942780: 44942780
3 SIX3 NM_005413.3(SIX3): c.770G> C (p.Arg257Pro) single nucleotide variant Pathogenic rs121917879 GRCh37 Chromosome 2, 45170013: 45170013
4 SIX3 NM_005413.3(SIX3): c.770G> C (p.Arg257Pro) single nucleotide variant Pathogenic rs121917879 GRCh38 Chromosome 2, 44942874: 44942874
5 SIX3 NM_005413.3(SIX3): c.749T> C (p.Val250Ala) single nucleotide variant Pathogenic rs121917880 GRCh37 Chromosome 2, 45169992: 45169992
6 SIX3 NM_005413.3(SIX3): c.749T> C (p.Val250Ala) single nucleotide variant Pathogenic rs121917880 GRCh38 Chromosome 2, 44942853: 44942853
7 SIX3 SIX3, 2-BP INS, 557GG insertion Pathogenic
8 SIX3 NM_005413.3(SIX3): c.406_407dup (p.Val137Profs) duplication no interpretation for the single variant rs753473749 GRCh37 Chromosome 2, 45169649: 45169650
9 SIX3 NM_005413.3(SIX3): c.406_407dup (p.Val137Profs) duplication no interpretation for the single variant rs753473749 GRCh38 Chromosome 2, 44942510: 44942511
10 SIX3 NM_005413.3(SIX3): c.206G> A (p.Gly69Asp) single nucleotide variant no interpretation for the single variant rs121917881 GRCh37 Chromosome 2, 45169449: 45169449
11 SIX3 NM_005413.3(SIX3): c.206G> A (p.Gly69Asp) single nucleotide variant no interpretation for the single variant rs121917881 GRCh38 Chromosome 2, 44942310: 44942310
12 SIX3 NM_005413.3(SIX3): c.339G> T (p.Trp113Cys) single nucleotide variant Pathogenic rs137853021 GRCh37 Chromosome 2, 45169582: 45169582
13 SIX3 NM_005413.3(SIX3): c.339G> T (p.Trp113Cys) single nucleotide variant Pathogenic rs137853021 GRCh38 Chromosome 2, 44942443: 44942443
14 SIX3 NM_005413.3(SIX3): c.385G> T (p.Glu129Ter) single nucleotide variant Pathogenic rs387906867 GRCh37 Chromosome 2, 45169628: 45169628
15 SIX3 NM_005413.3(SIX3): c.385G> T (p.Glu129Ter) single nucleotide variant Pathogenic rs387906867 GRCh38 Chromosome 2, 44942489: 44942489
16 SIX3 NM_005413.3(SIX3): c.109G> T (p.Gly37Cys) single nucleotide variant Conflicting interpretations of pathogenicity rs199823175 GRCh37 Chromosome 2, 45169352: 45169352
17 SIX3 NM_005413.3(SIX3): c.109G> T (p.Gly37Cys) single nucleotide variant Conflicting interpretations of pathogenicity rs199823175 GRCh38 Chromosome 2, 44942213: 44942213
18 SIX3 NM_005413.3(SIX3): c.219C> T (p.Pro73=) single nucleotide variant Likely benign rs186163123 GRCh37 Chromosome 2, 45169462: 45169462
19 SIX3 NM_005413.3(SIX3): c.219C> T (p.Pro73=) single nucleotide variant Likely benign rs186163123 GRCh38 Chromosome 2, 44942323: 44942323
20 SIX3 NM_005413.3(SIX3): c.576C> T (p.Arg192=) single nucleotide variant Benign rs182881 GRCh37 Chromosome 2, 45169819: 45169819
21 SIX3 NM_005413.3(SIX3): c.576C> T (p.Arg192=) single nucleotide variant Benign rs182881 GRCh38 Chromosome 2, 44942680: 44942680
22 SIX3 NM_005413.3(SIX3): c.696_705delCCCCAGCAAG (p.Asn232Lysfs) deletion Pathogenic rs397515502 GRCh37 Chromosome 2, 45169939: 45169948
23 SIX3 NM_005413.3(SIX3): c.696_705delCCCCAGCAAG (p.Asn232Lysfs) deletion Pathogenic rs397515502 GRCh38 Chromosome 2, 44942800: 44942809
24 SIX3 NM_005413.3(SIX3): c.90G> T (p.Ala30=) single nucleotide variant Benign rs78018362 GRCh37 Chromosome 2, 45169333: 45169333
25 SIX3 NM_005413.3(SIX3): c.90G> T (p.Ala30=) single nucleotide variant Benign rs78018362 GRCh38 Chromosome 2, 44942194: 44942194
26 SIX3: c.942G> A single nucleotide variant Benign
27 SIX3 NM_005413.3(SIX3): c.525G> A (p.Gln175=) single nucleotide variant Benign/Likely benign rs116680477 GRCh37 Chromosome 2, 45169768: 45169768
28 SIX3 NM_005413.3(SIX3): c.525G> A (p.Gln175=) single nucleotide variant Benign/Likely benign rs116680477 GRCh38 Chromosome 2, 44942629: 44942629
29 SIX3 NM_005413.3(SIX3): c.127G> T (p.Gly43Cys) single nucleotide variant Uncertain significance rs1436891421 GRCh37 Chromosome 2, 45169370: 45169370
30 SIX3 NM_005413.3(SIX3): c.127G> T (p.Gly43Cys) single nucleotide variant Uncertain significance rs1436891421 GRCh38 Chromosome 2, 44942231: 44942231
31 SIX3 NM_005413.3(SIX3): c.887C> G (p.Ser296Trp) single nucleotide variant Uncertain significance rs751280287 GRCh38 Chromosome 2, 44944648: 44944648
32 SIX3 NM_005413.3(SIX3): c.887C> G (p.Ser296Trp) single nucleotide variant Uncertain significance rs751280287 GRCh37 Chromosome 2, 45171787: 45171787
33 SIX3 NM_005413.3(SIX3): c.169G> T (p.Gly57Cys) single nucleotide variant Uncertain significance rs1344650194 GRCh37 Chromosome 2, 45169412: 45169412
34 SIX3 NM_005413.3(SIX3): c.169G> T (p.Gly57Cys) single nucleotide variant Uncertain significance rs1344650194 GRCh38 Chromosome 2, 44942273: 44942273
35 SIX3 NM_005413.3(SIX3): c.441_451del (p.Leu148Profs) deletion Pathogenic rs1553337688 GRCh38 Chromosome 2, 44942545: 44942555
36 SIX3 NM_005413.3(SIX3): c.441_451del (p.Leu148Profs) deletion Pathogenic rs1553337688 GRCh37 Chromosome 2, 45169684: 45169694
37 SIX3 NM_005413.3(SIX3): c.507G> A (p.Trp169Ter) single nucleotide variant Pathogenic GRCh38 Chromosome 2, 44942611: 44942611
38 SIX3 NM_005413.3(SIX3): c.507G> A (p.Trp169Ter) single nucleotide variant Pathogenic GRCh37 Chromosome 2, 45169750: 45169750
39 SIX3 NM_005413.3(SIX3): c.52A> T (p.Asn18Tyr) single nucleotide variant Uncertain significance GRCh37 Chromosome 2, 45169295: 45169295
40 SIX3 NM_005413.3(SIX3): c.52A> T (p.Asn18Tyr) single nucleotide variant Uncertain significance GRCh38 Chromosome 2, 44942156: 44942156

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 NR4A3 SIX1 SIX4

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 NR4A3 SIX1 SIX3 SIX4 SIX6

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

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

Sources for Holoprosencephaly 2

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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