HPE1
MCID: HLP023
MIFTS: 44

Holoprosencephaly 1 (HPE1)

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

Aliases & Classifications for Holoprosencephaly 1

MalaCards integrated aliases for Holoprosencephaly 1:

Name: Holoprosencephaly 1 57 12 29 6 15
Arhinencephaly 57 40 72 33
Cyclopia 57 55
Hpe1 57 12
Holoprosencephaly, Familial Alobar 57
Hpe, Familial; Hpec 57
Holoprosencephaly-1 13
Demyer Sequence 57
Hpe, Familial 57
Hpec 57

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
isolated cases



Classifications:



External Ids:

Disease Ontology 12 DOID:0110881
ICD10 33 Q04.1
MedGen 42 C0266667
UMLS 72 C0078982

Summaries for Holoprosencephaly 1

OMIM : 57 Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain and occurs after failed or abbreviated midline cleavage of the developing brain during the third and fourth weeks of gestation. HPE occurs in up to 1 in 250 gestations, but only 1 in 8,000 live births (Lacbawan et al., 2009). Classically, 3 degrees of severity defined by the extent of brain malformation have been described. In the most severe form, 'alobar HPE,' there is a single ventricle and no interhemispheric fissure. The olfactory bulbs and tracts and the corpus callosum are typically absent. In 'semilobar HPE,' the most common type of HPE in neonates who survive, there is partial cortical separation with rudimentary cerebral hemispheres and a single ventricle. In 'lobar HPE,' the ventricles are separated, but there is incomplete frontal cortical separation (Corsello et al., 1990). An additional milder form, called 'middle interhemispheric variant' (MIHV) has also been delineated, in which the posterior frontal and parietal lobes are incompletely separated and the corpus callosum may be hypoplastic (Lacbawan et al., 2009). Finally, microforms of HPE include a single maxillary median incisor or hypotelorism without the typical brain malformations (summary by Mercier et al., 2011). Cohen (2001) discussed problems in the definition of holoprosencephaly, which can be viewed from 2 different perspectives: anatomic (fixed) and genetic (broad). When the main interest is description, the anatomic perspective is appropriate. In genetic perspective, a fixed definition of holoprosencephaly is not appropriate because the same mutational cause may result in either holoprosencephaly or some microform of holoprosencephaly. Cohen (2001) concluded that both fixed and broad definitions are equally valid and depend on context. Munke (1989) provided an extensive review of the etiology and pathogenesis of holoprosencephaly, emphasizing heterogeneity. See also schizencephaly (269160), which may be part of the phenotypic spectrum of HPE. (236100)

MalaCards based summary : Holoprosencephaly 1, also known as arhinencephaly, is related to chromosome 18p deletion syndrome and lobar holoprosencephaly. An important gene associated with Holoprosencephaly 1 is HPE1 (Holoprosencephaly 1, Alobar), and among its related pathways/superpathways is Signaling events mediated by the Hedgehog family. The drugs Cisplatin and Doxorubicin have been mentioned in the context of this disorder. Affiliated tissues include brain, parietal lobe and olfactory bulb, and related phenotypes are agenesis of corpus callosum and intellectual disability

Disease Ontology : 12 A holoprosencephaly that has material basis in variation in the chromosome region 21q22.3.

Related Diseases for Holoprosencephaly 1

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 1 via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 113)
# Related Disease Score Top Affiliating Genes
1 chromosome 18p deletion syndrome 30.5 SIX3 SHH
2 lobar holoprosencephaly 30.3 SIX3 SHH GAS1
3 semilobar holoprosencephaly 30.3 SIX3 SHH GAS1
4 alobar holoprosencephaly 30.2 SIX3 SHH GAS1
5 holoprosencephaly 29.0 TRAPPC10 SIX3 SHH LSS HPE1 GAS1
6 isolated arhinencephaly 12.4
7 iniencephaly 11.5
8 charge syndrome 11.3
9 holoprosencephaly 9 11.3
10 holoprosencephaly 12 with or without pancreatic agenesis 11.3
11 hartsfield syndrome 11.2
12 xk aprosencephaly 11.2
13 nonsyndromic holoprosencephaly 11.2
14 midline interhemispheric variant of holoprosencephaly 10.3 SIX3 SHH GAS1
15 septopreoptic holoprosencephaly 10.3 SIX3 SHH GAS1
16 polydactyly 10.3
17 microform holoprosencephaly 10.3 SIX3 SHH GAS1
18 chromosomal triplication 10.3
19 ancylostomiasis 10.3 SERPINA1 MT-CO1
20 diphyllobothriasis 10.2 SERPINA1 MT-CO1
21 anencephaly 10.2
22 sirenomelia 10.2
23 triploidy 10.2
24 coloboma of macula 10.2
25 neural tube defects 10.2
26 hydrocephalus 10.2
27 cleft lip 10.2
28 congenital hydrocephalus 10.2
29 cleft lip/palate 10.2
30 cerebral malformation 10.2
31 mucinous cystadenofibroma 10.1 SERPINA1 CEACAM5
32 hair whorl 10.1
33 chromosome 2q35 duplication syndrome 10.1
34 agnathia-otocephaly complex 10.1
35 anodontia 10.1
36 cystic lymphangioma 10.1
37 arrhinia 10.1
38 chromosome 3p duplication 10.1
39 rapidly involuting congenital hemangioma 10.1
40 cleft palate, isolated 10.0
41 microgastria-limb reduction defects association 10.0
42 hemifacial microsomia 10.0
43 c syndrome 10.0
44 cerebellar hypoplasia 10.0
45 congenital heart defects, hamartomas of tongue, and polysyndactyly 10.0
46 fryns syndrome 10.0
47 mosaic variegated aneuploidy syndrome 1 10.0
48 microphthalmia 10.0
49 patau syndrome 10.0
50 orbital cyst 10.0

Graphical network of the top 20 diseases related to Holoprosencephaly 1:



Diseases related to Holoprosencephaly 1

Symptoms & Phenotypes for Holoprosencephaly 1

Human phenotypes related to Holoprosencephaly 1:

32 (show all 23)
# Description HPO Frequency HPO Source Accession
1 agenesis of corpus callosum 32 HP:0001274
2 intellectual disability 32 HP:0001249
3 seizures 32 HP:0001250
4 global developmental delay 32 HP:0001263
5 microcephaly 32 HP:0000252
6 short stature 32 HP:0004322
7 hypoglycemia 32 HP:0001943
8 generalized hypotonia 32 HP:0001290
9 cerebellar hypoplasia 32 HP:0001321
10 microphthalmia 32 HP:0000568
11 diabetes insipidus 32 HP:0000873
12 micropenis 32 HP:0000054
13 midface retrusion 32 HP:0011800
14 hypotelorism 32 HP:0000601
15 facial cleft 32 HP:0002006
16 median cleft lip and palate 32 HP:0008501
17 cyclopia 32 HP:0009914
18 adrenal hypoplasia 32 HP:0000835
19 aplasia of the nose 32 HP:0009927
20 single ventricle 32 HP:0001750
21 proboscis 32 HP:0012806
22 alobar holoprosencephaly 32 HP:0006988
23 ethmocephaly 32 HP:0030779

Symptoms via clinical synopsis from OMIM:

57
Neurologic Central Nervous System:
seizures
cerebellar hypoplasia
developmental delay
hypotonia
agenesis of the corpus callosum
more
Growth Height:
short stature

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

Head And Neck Head:
microcephaly
ethmocephaly
cebocephaly

Head And Neck Eyes:
microphthalmia
cyclopia
ocular hypotelorism
colobomata
varying degrees of doubling of intrinsic ocular structures

Head And Neck Face:
facial cleft
midface hypoplasia
premaxillary agenesis

Head And Neck Mouth:
median cleft lip/palate

Clinical features from OMIM:

236100

MGI Mouse Phenotypes related to Holoprosencephaly 1:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 vision/eye MP:0005391 9.17 AIRE CSTB GAS1 LSS SHH SIX3

Drugs & Therapeutics for Holoprosencephaly 1

Drugs for Holoprosencephaly 1 (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):


# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Cisplatin Approved Phase 2 15663-27-1 84093 441203 2767
2
Doxorubicin Approved, Investigational Phase 2 23214-92-8 31703
3
Liposomal doxorubicin Phase 2 31703

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Hyperthermic Intraperitoneal Chemotherapy in Ovarian Carcinoma Clinical Stage IIIC and IV During Interval Laparotomy. Phase II Study Recruiting NCT03275194 Phase 2
2 Genetic Analysis of Brain Disorders Recruiting NCT00645645

Search NIH Clinical Center for Holoprosencephaly 1

Genetic Tests for Holoprosencephaly 1

Genetic tests related to Holoprosencephaly 1:

# Genetic test Affiliating Genes
1 Holoprosencephaly 1 29

Anatomical Context for Holoprosencephaly 1

MalaCards organs/tissues related to Holoprosencephaly 1:

41
Brain, Parietal Lobe, Olfactory Bulb, Pituitary, Bone, Adrenal Gland, Eye

Publications for Holoprosencephaly 1

Articles related to Holoprosencephaly 1:

(show top 50) (show all 161)
# Title Authors PMID Year
1
FAMILIAL ALOBAR HOLOPROSENCEPHALY (ARHINENCEPHALY) WITH MEDIAN CLEFT LIP AND PALATE. REPORT OF PATIENT WITH 46 CHROMOSOMES. 38 8
14079950 1963
2
Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH. 71
21842183 2012
3
Cyclopia: an epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research. 8
22006661 2011
4
New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. 8
21940735 2011
5
A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum. 8
21976454 2011
6
Holoprosencephaly and holoprosencephaly-like phenotype and GAS1 DNA sequence changes: Report of four Brazilian patients. 71
20583177 2010
7
Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. 8
19346217 2009
8
Mesiodens, a new microform of holoprosencephaly? 8
19161155 2009
9
Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. 8
17525797 2007
10
Factor analysis of neuroanatomical and clinical characteristics of holoprosencephaly. 8
16503393 2006
11
The cyclopes in Odysseus' Apologos. 8
16145687 2005
12
Phenotypic and molecular variability of the holoprosencephalic spectrum. 8
15266610 2004
13
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
14
Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. 8
12395298 2002
15
Autosomal recessive alobar holoprosencephaly with essentially normal faces. 8
12239716 2002
16
Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases. 8
11851965 2002
17
Problems in the definition of holoprosencephaly. 8
11745988 2001
18
Holoprosencephaly Overview 71
20301702 2000
19
Mutations in holoprosencephaly. 8
10923031 2000
20
The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. 8
10556296 1999
21
Holoprosencephaly: a paradigm for the complex genetics of brain development. 8
9728329 1998
22
Segregation analysis in nonsyndromic holoprosencephaly. 8
9605287 1998
23
Physical mapping of the holoprosencephaly critical region in 18p11.3. 8
7485158 1995
24
Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome. 8
7485157 1995
25
Holoprosencephaly: a family showing dominant inheritance and variable expression. 8
8423605 1993
26
Holoprosencephaly: examples of clinical variability and etiologic heterogeneity. 8
2147361 1990
27
Holoprosencephaly in an infant with a minute deletion of chromosome 21(q22.3). 8
2363428 1990
28
Chromosome 7 abnormalities in parents of children with holoprosencephaly and hydronephrosis. 8
2309771 1990
29
Clinical, cytogenetic, and molecular approaches to the genetic heterogeneity of holoprosencephaly. 8
2683787 1989
30
Holoprosencephaly: variation of expression in face and brain in three sibs. 8
2751762 1989
31
Autosomal dominant inheritance of the DeMyer Sequence. 8
3209682 1988
32
Cyclopia and congenital cytomegalovirus infection. 8
2823607 1987
33
Holoprosencephaly in infants of diabetic mothers. 8
6834191 1983
34
[Familial occurrence of cyclops over several generations]. 8
6820862 1982
35
Holoprosencephaly in monozygotic twins - clinical and computer tomographic findings. 8
7195648 1981
36
Holoprosencephaly and endocrine dysgenesis in brothers. 8
7193414 1980
37
Genetic heterogeneity of cebocephaly. 8
4837285 1974
38
Letter: Hypothalamo-pituitary dysfunction in siblings of patients with holoprosencephaly. 8
4757527 1973
39
Familial cebocephaly. Case description and survey of the anomaly. 8
5454670 1970
40
Familial holoprosencephaly. 8
5309311 1970
41
Cyclopism as a hereditary malformation. 8
5647374 1968
42
Familial holoprosencephaly with endocrine dysgenesis. 8
4294576 1968
43
[Familial incidence of malformations of the arhinencephalia group]. 8
13723646 1961
44
[Familial findings in lethal anomalies of the human body]. 8
13113863 1954
45
Fetal MRI findings in a retrospective cohort of 26 cases of prenatally diagnosed CHARGE syndrome individuals. 38
30715739 2019
46
Duplicated distal phalanx of thumb or hallux in trisomy 13: A recurrent feature in a series of 42 fetuses. 38
30328679 2018
47
Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome. 38
29178447 2017
48
A Possible Link Between Pyriproxyfen and Microcephaly. 38
29362686 2017
49
Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry. 38
26543002 2015
50
Inversion duplication deletions involving the long arm of chromosome 13: phenotypic description of additional three fetuses and genotype-phenotype correlation. 38
24975584 2014

Variations for Holoprosencephaly 1

ClinVar genetic disease variations for Holoprosencephaly 1:

6
# Gene Variation Type Significance SNP ID GRCh37 Pos GRCh38 Pos
1 GAS1 NM_002048.3(GAS1): c.776G> A (p.Gly259Glu) single nucleotide variant Uncertain significance rs387907166 9:89560919-89560919 9:86946004-86946004
2 GAS1 NM_002048.3(GAS1): c.599C> G (p.Thr200Arg) single nucleotide variant Uncertain significance rs387907165 9:89561096-89561096 9:86946181-86946181

Expression for Holoprosencephaly 1

Search GEO for disease gene expression data for Holoprosencephaly 1.

Pathways for Holoprosencephaly 1

Pathways related to Holoprosencephaly 1 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
10.1 SHH GAS1

GO Terms for Holoprosencephaly 1

Biological processes related to Holoprosencephaly 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 regulation of cell proliferation GO:0042127 9.54 SIX3 SHH CELA1
2 developmental growth GO:0048589 9.32 SHH GAS1
3 anatomical structure development GO:0048856 9.26 SIX3 SHH
4 embryonic pattern specification GO:0009880 9.16 SIM2 SHH
5 negative thymic T cell selection GO:0045060 8.96 SHH AIRE
6 telencephalon regionalization GO:0021978 8.62 SIX3 SHH

Molecular functions related to Holoprosencephaly 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 serine-type peptidase activity GO:0008236 8.8 CELA3B CELA3A CELA1

Sources for Holoprosencephaly 1

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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