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HPE
MCID: HLP001
MIFTS: 68

Holoprosencephaly (HPE)

Categories: Endocrine diseases, Fetal diseases, Genetic diseases, Neuronal diseases, Rare diseases
Genes Variations Tissues Related diseases Publications Pathways Symptoms & Phenotypes
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Aliases & Classifications for Holoprosencephaly

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MalaCards integrated aliases for Holoprosencephaly:

Name: Holoprosencephaly 12 74 24 52 53 58 36 54 43 15 39 32
Holoprosencephaly Sequence 12 29 6
Hpe 52 58

Characteristics:

Orphanet epidemiological data:

58
holoprosencephaly
Inheritance: Multigenic/multifactorial,Not applicable; Prevalence: 1-5/10000 (Europe); Age of onset: Antenatal,Neonatal; Age of death: any age;

Classifications:

MalaCards categories:
Global: Rare diseases Fetal diseases Genetic diseases
Anatomical: Neuronal diseases Endocrine diseases
See all MalaCards categories (disease lists)
ICD10: 32 33
Orphanet: 58  
Rare neurological diseases
Rare endocrine diseases
Developmental anomalies during embryogenesis


Sources

Summaries for Holoprosencephaly

About this section
NINDS : 53 Holoprosencephaly is a disorder caused by the failure of the prosencephalon (the embryonic forebrain) to sufficiently divide into the double lobes of the cerebral hemispheres. The result is a single-lobed brain structure and severe skull and facial defects. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip. There are three classifications of holoprosencephaly. Alobar, in which the brain has not divided at all, is usually associated with severe facial deformities. Semilobar, in which the brain's hemispheres have somewhat divided, causes an intermediate form of the disorder. Lobar, in which there is considerable evidence of separate brain hemispheres, is the least severe form. In some cases of lobar holoprosencephaly the baby's brain may be nearly normal. The least severe of the facial anomalies is the median cleft lip (premaxillary agenesis). The most severe is cyclopia, an abnormality characterized by a single eye located in the area normally occupied by the root of the nose, and a missing nose or a proboscis (a tubular-shaped nose) located above the eye. The least common facial anomaly is ethmocephaly, in which a proboscis separates closely-set eyes. Cebocephaly, another facial anomaly, is characterized by a small, flattened nose with a single nostril situated below incomplete or underdeveloped closely-set eyes.

MalaCards based summary : Holoprosencephaly, also known as holoprosencephaly sequence, is related to holoprosencephaly 9 and holoprosencephaly 3. An important gene associated with Holoprosencephaly is FGFR1 (Fibroblast Growth Factor Receptor 1), and among its related pathways/superpathways are Hedgehog signaling pathway and Pathways in cancer. Affiliated tissues include Primitive Streak, brain and pituitary, and related phenotypes are abnormal facial shape and holoprosencephaly

Disease Ontology : 12 A congenital nervous system abnormality characterized by failed or incomplete separation of the forebrain early in gestation; it is accompanied by a spectrum of characteristic craniofacial anomalies.

NIH Rare Diseases : 52 Holoprosencephaly is an abnormality of brain development in which the brain doesn't properly divide into the right and left hemispheres. The condition can also affect development of the head and face. There are 4 types of holoprosencephaly, distinguished by severity. From most to least severe, the 4 types are alobar, semi-lobar, lobar, and middle interhemispheric variant (MIHV). In general, the severity of any facial defects corresponds to the severity of the brain defect. The most severely affected people have one central eye (cyclopia) and a tubular nasal structure (proboscis) located above the eye. In the less severe forms, the brain is only partially divided, and the eyes usually are set close together. Other signs and symptoms often include intellectual disability and pituitary gland problems . Holoprosencephaly can be caused by mutations in any of at least 14 different genes ; chromosome abnormalities; or agents that can cause birth defects (teratogens ). It may also be a feature of several unique genetic syndromes . In many cases, the exact cause is unknown. Life expectancy for people with this condition varies, and treatment depends on the symptoms and severity in each person.

KEGG : 36 Holoprosencephaly (HPE) is characterized by incomplete separation of forebrain and facial components into left and right sides.

Wikipedia : 74 Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo)... more...

GeneReviews: NBK1530
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Related Diseases for Holoprosencephaly

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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 via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 397)
# Related Disease Score Top Affiliating Genes
1 holoprosencephaly 9 35.2 ZIC2 SIX3 PTCH1 GLI2 FOXH1 DISP1
2 holoprosencephaly 3 35.1 ZIC2 SIX3 SHH GLI2 DISP1
3 holoprosencephaly 7 35.1 ZIC2 SIX3 PTCH1 FOXH1 DISP1
4 holoprosencephaly 2 35.0 ZIC2 SIX3 SHH PTCH1 GLI2 FOXH1
5 holoprosencephaly 1 35.0 ZIC2 TRAPPC10 SIX3 SHH HPE1 GLI2
6 holoprosencephaly 5 35.0 ZIC2 SIX3 SHH PTCH1 LOC110008580 GLI2
7 holoprosencephaly 4 35.0 ZIC2 TGIF1 SIX3 SHH GLI2 FOXH1
8 holoprosencephaly 8 34.9 ZIC2 HPE8 DISP1 CDON
9 holoprosencephaly 11 34.9 ZIC2 TRAPPC10 SIX3 SHH PTCH1 GLI2
10 semilobar holoprosencephaly 34.6 ZIC2 TGIF1 SIX3 SHH PTCH1 NODAL
11 alobar holoprosencephaly 34.5 ZIC2 TGIF1 SIX3 SHH PTCH1 NODAL
12 lobar holoprosencephaly 34.5 ZIC2 TGIF1 SIX3 SHH PTCH1 NODAL
13 microform holoprosencephaly 34.5 ZIC2 TGIF1 SIX3 SHH PTCH1 NODAL
14 holoprosencephaly, recurrent infections, and monocytosis 34.5 SIX3 PTCH1 GLI2
15 hartsfield syndrome 34.5 FGFR1 FGF8
16 midline interhemispheric variant of holoprosencephaly 34.5 ZIC2 TGIF1 SIX3 SHH PTCH1 NODAL
17 septopreoptic holoprosencephaly 34.4 ZIC2 TGIF1 SIX3 SHH PTCH1 NODAL
18 patau syndrome 32.0 ZIC2 SIX3 SHH NODAL FOXH1 DISP1
19 cleft palate, isolated 31.8 SHH PTCH1 GLI2 FGFR1 FGF8
20 microcephaly 31.5 ZIC2 ZIC1 SHH PTCH1 GLI2 DHCR7
21 septooptic dysplasia 31.4 SIX3 SHH GLI2 FGFR1 FGF8
22 coloboma of macula 31.4 ZIC2 SIX3 SHH PTCH1 FGFR1 FGF8
23 craniosynostosis 31.3 ZIC1 PTCH1 FGFR1 FGF8
24 neural tube defects 31.3 ZIC2 ZIC1 SHH PTCH1 FGF8
25 hypopituitarism 31.2 SIX3 SHH GLI2
26 basal cell nevus syndrome 31.1 SHH PTCH1 GLI2 GAS1 CDON
27 pallister-hall syndrome 31.1 ZIC2 SIX3 SHH PTCH1 GLI2 GAS1
28 orofacial cleft 31.0 ZIC2 SIX3 SHH PTCH1 GLI2 FGFR1
29 chromosome 2q35 duplication syndrome 30.9 SHH PTCH1 FGFR1 FGF8 DHCR7
30 synostosis 30.9 SHH FGFR1 FGF8
31 tetralogy of fallot 30.9 SHH NODAL FOXH1 FGF8
32 congenital hypopituitarism 30.8 SIX3 SHH GLI2
33 pituitary stalk interruption syndrome 30.7 TGIF1 SHH CDON
34 anus, imperforate 30.7 SHH GLI2 FGF8
35 double outlet right ventricle 30.6 NODAL FOXH1 FGF8
36 charge syndrome 30.6 SHH FGFR1 FGF8
37 pfeiffer syndrome 30.4 FGFR1 FGF8 DHCR7
38 nonsyndromic holoprosencephaly 12.7
39 holoprosencephaly, semilobar, with craniosynostosis 12.6
40 holoprosencephaly 12 with or without pancreatic agenesis 12.6
41 holoprosencephaly with fetal akinesia/hypokinesia sequence 12.6
42 holoprosencephaly 6 12.5
43 brachial amelia, cleft lip, and holoprosencephaly 12.5
44 agnathia-otocephaly complex 12.3
45 holoprosencephaly-caudal dysgenesis syndrome 12.2
46 obsolete: congenital nasal pyriform aperture stenosis with holoprosencephaly 12.1
47 pseudotrisomy 13 syndrome 12.1
48 pancreatic agenesis-holoprosencephaly syndrome 12.1
49 steinfeld syndrome 12.0
50 chromosome 1q41-q42 deletion syndrome 11.7

Graphical network of the top 20 diseases related to Holoprosencephaly:



Diseases related to Holoprosencephaly
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Symptoms & Phenotypes for Holoprosencephaly

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Human phenotypes related to Holoprosencephaly:

58 31 (show top 50) (show all 93)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 abnormal facial shape 58 31 hallmark (90%) Very frequent (99-80%) HP:0001999
2 holoprosencephaly 58 31 hallmark (90%) Very frequent (99-80%) HP:0001360
3 median cleft lip and palate 58 31 hallmark (90%) Very frequent (99-80%) HP:0008501
4 single median maxillary incisor 58 31 hallmark (90%) Very frequent (99-80%) HP:0006315
5 bilateral cleft lip 58 31 hallmark (90%) Very frequent (99-80%) HP:0100336
6 seizures 58 31 frequent (33%) Frequent (79-30%) HP:0001250
7 spasticity 58 31 frequent (33%) Frequent (79-30%) HP:0001257
8 diabetes mellitus 58 31 frequent (33%) Frequent (79-30%) HP:0000819
9 muscular hypotonia 58 31 frequent (33%) Frequent (79-30%) HP:0001252
10 muscle weakness 58 31 frequent (33%) Frequent (79-30%) HP:0001324
11 global developmental delay 58 31 frequent (33%) Frequent (79-30%) HP:0001263
12 microcephaly 58 31 frequent (33%) Frequent (79-30%) HP:0000252
13 gastroesophageal reflux 58 31 frequent (33%) Frequent (79-30%) HP:0002020
14 cognitive impairment 58 31 frequent (33%) Frequent (79-30%) HP:0100543
15 hypoglycemia 58 31 frequent (33%) Frequent (79-30%) HP:0001943
16 dystonia 58 31 frequent (33%) Frequent (79-30%) HP:0001332
17 depressed nasal ridge 58 31 frequent (33%) Frequent (79-30%) HP:0000457
18 microphthalmia 58 31 frequent (33%) Frequent (79-30%) HP:0000568
19 choanal atresia 58 31 frequent (33%) Frequent (79-30%) HP:0000453
20 anosmia 58 31 frequent (33%) Frequent (79-30%) HP:0000458
21 iris coloboma 58 31 frequent (33%) Frequent (79-30%) HP:0000612
22 anophthalmia 58 31 frequent (33%) Frequent (79-30%) HP:0000528
23 reduced number of teeth 58 31 frequent (33%) Frequent (79-30%) HP:0009804
24 hypotelorism 58 31 frequent (33%) Frequent (79-30%) HP:0000601
25 aplasia/hypoplasia of the corpus callosum 58 31 frequent (33%) Frequent (79-30%) HP:0007370
26 hyposmia 58 31 frequent (33%) Frequent (79-30%) HP:0004409
27 cyclopia 58 31 frequent (33%) Frequent (79-30%) HP:0009914
28 macrocephaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0000256
29 hypertelorism 58 31 occasional (7.5%) Occasional (29-5%) HP:0000316
30 short neck 58 31 occasional (7.5%) Occasional (29-5%) HP:0000470
31 frontal bossing 58 31 occasional (7.5%) Occasional (29-5%) HP:0002007
32 scoliosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0002650
33 ptosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0000508
34 constipation 58 31 occasional (7.5%) Occasional (29-5%) HP:0002019
35 hydrocephalus 58 31 occasional (7.5%) Occasional (29-5%) HP:0000238
36 chorea 58 31 occasional (7.5%) Occasional (29-5%) HP:0002072
37 respiratory insufficiency 58 31 occasional (7.5%) Occasional (29-5%) HP:0002093
38 macrotia 58 31 occasional (7.5%) Occasional (29-5%) HP:0000400
39 brachydactyly 58 31 occasional (7.5%) Occasional (29-5%) HP:0001156
40 cryptorchidism 58 31 occasional (7.5%) Occasional (29-5%) HP:0000028
41 ventricular septal defect 58 31 occasional (7.5%) Occasional (29-5%) HP:0001629
42 anteverted nares 58 31 occasional (7.5%) Occasional (29-5%) HP:0000463
43 thick eyebrow 58 31 occasional (7.5%) Occasional (29-5%) HP:0000574
44 optic atrophy 58 31 occasional (7.5%) Occasional (29-5%) HP:0000648
45 feeding difficulties in infancy 58 31 occasional (7.5%) Occasional (29-5%) HP:0008872
46 proteinuria 58 31 occasional (7.5%) Occasional (29-5%) HP:0000093
47 retinopathy 58 31 occasional (7.5%) Occasional (29-5%) HP:0000488
48 arrhythmia 58 31 occasional (7.5%) Occasional (29-5%) HP:0011675
49 broad philtrum 58 31 occasional (7.5%) Occasional (29-5%) HP:0000289
50 highly arched eyebrow 58 31 occasional (7.5%) Occasional (29-5%) HP:0002553

MGI Mouse Phenotypes related to Holoprosencephaly:

45 (show all 18)
# Description MGI Source Accession Score Top Affiliating Genes
1 craniofacial MP:0005382 10.42 CDON DHCR7 DISP1 FGF8 FGFR1 FOXH1
2 growth/size/body region MP:0005378 10.4 CDON DHCR7 DISP1 FGF8 FGFR1 FOXH1
3 behavior/neurological MP:0005386 10.39 CDON DHCR7 FGF8 FGFR1 GAS1 GLI2
4 cardiovascular system MP:0005385 10.38 CDON DHCR7 DISP1 FGF8 FGFR1 FOXH1
5 digestive/alimentary MP:0005381 10.35 CDON DHCR7 DISP1 FGF8 FGFR1 FOXH1
6 embryo MP:0005380 10.34 CDON DISP1 FGF8 FGFR1 FOXH1 GAS1
7 mortality/aging MP:0010768 10.31 CDON DHCR7 DISP1 FGF8 FGFR1 FOXH1
8 cellular MP:0005384 10.3 CDON DISP1 FGF8 FGFR1 GAS1 GLI2
9 nervous system MP:0003631 10.27 CDON DHCR7 DISP1 FGF8 FGFR1 FOXH1
10 limbs/digits/tail MP:0005371 10.23 CDON DHCR7 DISP1 FGF8 FGFR1 GAS1
11 endocrine/exocrine gland MP:0005379 10.16 DISP1 FGF8 FGFR1 FOXH1 GLI2 PTCH1
12 muscle MP:0005369 10.1 DHCR7 DISP1 FGF8 FGFR1 FOXH1 GLI2
13 hearing/vestibular/ear MP:0005377 10.08 FGF8 FGFR1 FOXH1 GAS1 GLI2 PTCH1
14 respiratory system MP:0005388 10.07 CDON DHCR7 DISP1 FGF8 FOXH1 GAS1
15 skeleton MP:0005390 10.03 CDON DISP1 FGF8 FGFR1 FOXH1 GAS1
16 normal MP:0002873 10.02 DISP1 FGF8 FGFR1 FOXH1 GLI2 NODAL
17 vision/eye MP:0005391 9.47 CDON DISP1 FGF8 FGFR1 FOXH1 GAS1
18 taste/olfaction MP:0005394 9.35 NODAL PTCH1 SHH SIX3 TGIF1
Sources

Drugs & Therapeutics for Holoprosencephaly

About this section

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 The Experiences and Needs of Parents Continuing a Pregnancy Following Abnormal Prenatal Results: The Case of Holoprosencephaly Completed NCT00005016
2 Genetic Analysis of Left-Right Axis Malformations Completed NCT00341133
3 Clinical and Genetic Studies on Holoprosencephaly Recruiting NCT00088426
4 Genetic Analysis of Brain Disorders Recruiting NCT00645645

Search NIH Clinical Center for Holoprosencephaly

Cochrane evidence based reviews: holoprosencephaly

Sources

Genetic Tests for Holoprosencephaly

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Genetic tests related to Holoprosencephaly:

# Genetic test Affiliating Genes
1 Holoprosencephaly Sequence 29 FOXH1
Sources

Anatomical Context for Holoprosencephaly

About this section

MalaCards organs/tissues related to Holoprosencephaly:

40
Brain, Pituitary, Eye, Heart, Bone, Kidney, Cerebellum
LifeMap Discovery
Data from LifeMap, the Embryonic Development and Stem Cells Database

Cells/anatomical compartments in embryo or adult related to Holoprosencephaly:
# Tissue Anatomical CompartmentCell Relevance
1 Primitive Streak Primitive Streak Affected by disease
Sources

Publications for Holoprosencephaly

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Articles related to Holoprosencephaly:

(show top 50) (show all 1900)
# Title Authors PMID Year
1
A novel SIX3 mutation segregates with holoprosencephaly in a large family. 54 61 24 6
19353631 2009
2
Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. 54 61 24 6
11479728 2001
3
Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. 54 61 24 6
10835638 2000
4
The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. 54 61 24 6
10556296 1999
5
Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH. 61 24 6
21842183 2012
6
Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. 61 24 6
21802063 2011
7
Holoprosencephaly and holoprosencephaly-like phenotype and GAS1 DNA sequence changes: Report of four Brazilian patients. 61 24 6
20583177 2010
8
Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. 61 24 6
19346217 2009
9
Mutations in the human SIX3 gene in holoprosencephaly are loss of function. 61 24 6
18791198 2008
10
SIX3 mutations with holoprosencephaly. 61 24 6
17001667 2006
11
GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum? 61 24 6
17096318 2006
12
Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. 61 24 6
14581620 2003
13
Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. 61 24 6
11919111 2002
14
Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. 61 24 6
10369266 1999
15
Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. 61 24 6
9771712 1998
16
Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. 61 24 6
9302262 1997
17
Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. 61 24 6
8896572 1996
18
PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI. 54 61 6
17001668 2006
19
A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. 24 6
15994174 2005
20
Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability. 54 61 6
12567406 2003
21
Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations. 54 61 6
12522553 2003
22
A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. 54 61 6
11039582 2000
23
Clinical findings in patients with GLI2 mutations--phenotypic variability. 61 6
21204792 2012
24
ZIC2 mutations are seen in holoprosencephaly and not partial rhombencephalosynapsis. 61 6
21990207 2011
25
Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2. 61 6
21638761 2011
26
Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. 61 6
20685856 2010
27
Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly. 61 6
20157829 2010
28
The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis. 54 61 24
19603532 2009
29
A sonic hedgehog missense mutation associated with holoprosencephaly causes defective binding to GAS1. 61 6
19478089 2009
30
Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. 54 61 24
18694563 2008
31
Cerebro-oculo-nasal syndrome: 13 new Brazilian cases. 61 6
17985375 2007
32
Functional analysis of mutations in TGIF associated with holoprosencephaly. 54 61 24
16962354 2007
33
Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. 61 6
16282375 2005
34
Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1. 61 6
15523651 2004
35
SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. 61 6
12709790 2003
36
Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. 61 6
11941477 2002
37
Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. 54 61 24
11285244 2001
38
Holoprosencephaly Overview 61 6
20301702 2000
39
Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. 54 61 24
10441331 1999
40
Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of Sonic Hedgehog? 54 61 24
8989473 1996
41
Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21. 54 61 24
8824878 1996
42
FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. 61 24
23812909 2013
43
High Intellectual Function in Individuals with Mutation-Positive Microform Holoprosencephaly. 61 24
23112757 2012
44
Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. 61 24
22791840 2012
45
Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions. 61 24
22310223 2012
46
A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum. 61 24
21976454 2011
47
New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. 61 24
21940735 2011
48
NOTCH, a new signaling pathway implicated in holoprosencephaly. 61 24
21196490 2011
49
Septopreoptic holoprosencephaly: a mild subtype associated with midline craniofacial anomalies. 61 24
20488907 2010
50
Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. 61 24
19955556 2010
Sources

Variations for Holoprosencephaly

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ClinVar genetic disease variations for Holoprosencephaly:

6 (show top 50) (show all 506) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 FGFR1 NM_023110.2(FGFR1):c.880G>A (p.Glu294Lys)SNV Pathogenic 517665 rs528376963 8:38282083-38282083 8:38424565-38424565
2 FGF8 NM_033164.4(FGF8):c.526_540del (p.Arg176_Gly180del)deletion Pathogenic 545457 rs1554834321 10:103530248-103530262 10:101770491-101770505
3 FGF8 NM_033164.4(FGF8):c.352C>T (p.Arg118Ter)SNV Pathogenic/Likely pathogenic 235082 rs876661330 10:103531279-103531279 10:101771522-101771522
4 FGF8 NM_033164.4(FGF8):c.323C>T (p.Thr108Met)SNV Likely pathogenic 235081 rs876661329 10:103531308-103531308 10:101771551-101771551
5 FGFR1 NM_023110.2(FGFR1):c.2074G>A (p.Glu692Lys)SNV Likely pathogenic 235088 rs876661335 8:38271782-38271782 8:38414264-38414264
6 FGF8 NM_033164.4(FGF8):c.584G>A (p.Arg195Gln)SNV Likely pathogenic 235083 rs876661331 10:103530204-103530204 10:101770447-101770447
7 MATN4 NM_003833.4(MATN4):c.515G>C (p.Gly172Ala)SNV Likely pathogenic 183295 rs730882210 20:43932996-43932996 20:45304356-45304356
8 FGF8 NM_033164.4(FGF8):c.365C>T (p.Thr122Met)SNV Likely pathogenic 545458 rs61730334 10:103531266-103531266 10:101771509-101771509
9 FGF8 NM_033164.4(FGF8):c.157-33G>CSNV Likely pathogenic 545459 rs1554834889 10:103534669-103534669 10:101774912-101774912
10 FGF8 NM_033164.4(FGF8):c.411+1G>ASNV Likely pathogenic 545517 rs1490604080 10:103531219-103531219 10:101771462-101771462
11 FGF8 NM_033164.4(FGF8):c.157-34G>ASNV Likely pathogenic 545413 rs1554834892 10:103534670-103534670 10:101774913-101774913
12 FGF8 NM_033164.4(FGF8):c.436G>T (p.Val146Phe)SNV Likely pathogenic 545456 rs139565972 10:103530352-103530352 10:101770595-101770595
13 ZIC2 NM_007129.5(ZIC2):c.1225C>T (p.Arg409Trp)SNV Likely pathogenic 635857 13:100637349-100637349 13:99985095-99985095
14 FGF8 NM_033164.4(FGF8):c.86_103dup (p.Gly29_Arg34dup)duplication Conflicting interpretations of pathogenicity 545463 rs762175290 10:103534939-103534940 10:101775182-101775183
15 PTCH1 NM_001083602.2(PTCH1):c.3954G>A (p.Pro1318=)SNV Conflicting interpretations of pathogenicity 367663 rs761887390 9:98209386-98209386 9:95447104-95447104
16 PTCH1 NM_001083602.2(PTCH1):c.2262C>T (p.Tyr754=)SNV Conflicting interpretations of pathogenicity 367667 rs766227557 9:98229498-98229498 9:95467216-95467216
17 PTCH1 NM_001083602.2(PTCH1):c.1649+14C>TSNV Conflicting interpretations of pathogenicity 367668 rs202007968 9:98232081-98232081 9:95469799-95469799
18 NODAL NM_018055.5(NODAL):c.281G>A (p.Arg94Gln)SNV Conflicting interpretations of pathogenicity 300307 rs146018217 10:72195652-72195652 10:70435896-70435896
19 CDON NM_016952.4(CDON):c.2462G>A (p.Arg821His)SNV Conflicting interpretations of pathogenicity 303497 rs146660717 11:125864848-125864848 11:125994953-125994953
20 TGIF1 NM_173208.2(TGIF1):c.723G>A (p.Pro241=)SNV Conflicting interpretations of pathogenicity 326710 rs114912664 18:3457842-3457842 18:3457844-3457844
21 TGIF1 NM_173208.2(TGIF1):c.573G>T (p.Ser191=)SNV Conflicting interpretations of pathogenicity 326709 rs142737563 18:3457692-3457692 18:3457694-3457694
22 PTCH1 NM_001083602.2(PTCH1):c.4-1726C>GSNV Conflicting interpretations of pathogenicity 188208 rs779791579 9:98270607-98270607 9:95508325-95508325
23 CDON NM_016952.4(CDON):c.1855G>C (p.Asp619His)SNV Conflicting interpretations of pathogenicity 193724 rs141081456 11:125873968-125873968 11:126004073-126004073
24 PTCH1 NM_001083602.2(PTCH1):c.1150-4G>ASNV Conflicting interpretations of pathogenicity 220126 rs772826555 9:98239988-98239988 9:95477706-95477706
25 PTCH1 NM_001083602.2(PTCH1):c.3829G>A (p.Gly1277Arg)SNV Conflicting interpretations of pathogenicity 41664 rs200100952 9:98209511-98209511 9:95447229-95447229
26 GLI2 NM_005270.4(GLI2):c.3469C>T (p.Leu1157=)SNV Conflicting interpretations of pathogenicity 194224 rs141988240 2:121746959-121746959 2:120989383-120989383
27 PTCH1 NM_001083602.2(PTCH1):c.3225G>A (p.Ala1075=)SNV Conflicting interpretations of pathogenicity 216382 rs745948150 9:98215786-98215786 9:95453504-95453504
28 PTCH1 NM_001083602.2(PTCH1):c.2494G>A (p.Asp832Asn)SNV Conflicting interpretations of pathogenicity 215694 rs531947455 9:98224149-98224149 9:95461867-95461867
29 PTCH1 NM_001083602.2(PTCH1):c.1018-6C>ASNV Conflicting interpretations of pathogenicity 216368 rs186008764 9:98240474-98240474 9:95478192-95478192
30 PTCH1 NM_001083602.2(PTCH1):c.2106C>T (p.Thr702=)SNV Conflicting interpretations of pathogenicity 135878 rs1805156 9:98229654-98229654 9:95467372-95467372
31 PTCH1 NM_001083602.2(PTCH1):c.2286C>T (p.Asn762=)SNV Conflicting interpretations of pathogenicity 135879 rs143305989 9:98229474-98229474 9:95467192-95467192
32 PTCH1 NM_001083602.2(PTCH1):c.2589C>T (p.Asn863=)SNV Conflicting interpretations of pathogenicity 135883 rs145196322 9:98221982-98221982 9:95459700-95459700
33 PTCH1 NM_001083602.2(PTCH1):c.2689+10G>ASNV Conflicting interpretations of pathogenicity 135886 rs202081420 9:98221872-98221872 9:95459590-95459590
34 PTCH1 NM_001083602.2(PTCH1):c.2072T>C (p.Phe691Ser)SNV Conflicting interpretations of pathogenicity 237468 rs547954117 9:98229688-98229688 9:95467406-95467406
35 PTCH1 NM_001083602.2(PTCH1):c.1986G>A (p.Thr662=)SNV Conflicting interpretations of pathogenicity 255674 rs201103723 9:98231099-98231099 9:95468817-95468817
36 PTCH1 NM_001083602.2(PTCH1):c.1512G>T (p.Leu504=)SNV Conflicting interpretations of pathogenicity 255671 rs374924167 9:98238334-98238334 9:95476052-95476052
37 TGIF1 NM_003244.3(TGIF1):c.123C>T (p.Asn41=)SNV Conflicting interpretations of pathogenicity 259014 rs138292737 18:3456458-3456458 18:3456460-3456460
38 GLI2 NM_005270.4(GLI2):c.4030C>T (p.Leu1344=)SNV Conflicting interpretations of pathogenicity 282213 rs149290823 2:121747520-121747520 2:120989944-120989944
39 GLI2 NM_005270.4(GLI2):c.2708C>G (p.Thr903Ser)SNV Conflicting interpretations of pathogenicity 285394 rs572826436 2:121746198-121746198 2:120988622-120988622
40 GLI2 NM_005270.4(GLI2):c.4497T>C (p.Thr1499=)SNV Conflicting interpretations of pathogenicity 330998 rs151090814 2:121747987-121747987 2:120990411-120990411
41 GLI2 NM_005270.4(GLI2):c.252C>T (p.His84=)SNV Conflicting interpretations of pathogenicity 330966 rs201412339 2:121685040-121685040 2:120927464-120927464
42 GLI2 NM_005270.4(GLI2):c.2250T>G (p.Thr750=)SNV Conflicting interpretations of pathogenicity 330977 rs146909860 2:121744147-121744147 2:120986571-120986571
43 GLI2 NM_005270.4(GLI2):c.595G>A (p.Gly199Ser)SNV Conflicting interpretations of pathogenicity 330967 rs542892514 2:121712958-121712958 2:120955382-120955382
44 GLI2 NM_005270.4(GLI2):c.845+10G>ASNV Conflicting interpretations of pathogenicity 330968 rs199673018 2:121726501-121726501 2:120968925-120968925
45 GLI2 NM_005270.4(GLI2):c.4221G>A (p.Pro1407=)SNV Conflicting interpretations of pathogenicity 330993 rs200149538 2:121747711-121747711 2:120990135-120990135
46 GLI2 NM_005270.4(GLI2):c.3460G>A (p.Val1154Ile)SNV Conflicting interpretations of pathogenicity 330986 rs200999705 2:121746950-121746950 2:120989374-120989374
47 GLI2 NM_005270.4(GLI2):c.148+5T>CSNV Conflicting interpretations of pathogenicity 330962 rs201273354 2:121555049-121555049 2:120797473-120797473
48 GLI2 NM_005270.4(GLI2):c.4344C>T (p.Tyr1448=)SNV Conflicting interpretations of pathogenicity 330996 rs374166743 2:121747834-121747834 2:120990258-120990258
49 PTCH1 NM_001083602.2(PTCH1):c.1610G>A (p.Arg537His)SNV Conflicting interpretations of pathogenicity 367669 rs199523893 9:98232134-98232134 9:95469852-95469852
50 CDON NM_016952.4(CDON):c.3190A>G (p.Ser1064Gly)SNV Conflicting interpretations of pathogenicity 303494 rs143111106 11:125851030-125851030 11:125981135-125981135

Copy number variations for Holoprosencephaly from CNVD:

7 (show all 17)
# CNVD ID Chromosome Start End Type Gene Symbol CNVD Disease
1 27741 1 212100000 222100000 Deletion DISP1 Holoprosencephaly
2 27742 10 53744046 53747423 Deletion DKK1 Holoprosencephaly
3 27743 2 121271336 121449155 Deletion GLI2 Holoprosencephaly
4 27745 1 212100000 222100000 Deletion PATCHED Holoprosencephaly
5 27746 7 155285496 155297728 Deletion SHH Holoprosencephaly
6 27747 1 212100000 222100000 Deletion SIL Holoprosencephaly
7 27748 2 45022540 45025894 Deletion SIX3 Holoprosencephaly
8 27749 1 212100000 222100000 Deletion SMOOTHENED Holoprosencephaly
9 27750 1 212100000 222100000 Deletion TGIF Holoprosencephaly
10 27751 13 99432319 99437020 Deletion ZIC2 Holoprosencephaly
11 80937 13 99432319 99437020 Microdeletion ZIC2 Holoprosencephaly
12 91539 15 31400000 37900000 Deletion Holoprosencephaly
13 93580 15 55800000 65300000 Deletion Holoprosencephaly
14 120908 18 3402071 3448406 Microdeletion TGIF Holoprosencephaly
15 146030 2 45022540 45025894 Microdeletion SIX3 Holoprosencephaly
16 210238 6 29900000 45200000 Gain Holoprosencephaly
17 222729 7 155285496 155297728 Microdeletion SHH Holoprosencephaly
Sources

Expression for Holoprosencephaly

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Search GEO for disease gene expression data for Holoprosencephaly.
Sources

Pathways for Holoprosencephaly

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Pathways related to Holoprosencephaly according to KEGG:

36
# Name Kegg Source Accession
1 Hedgehog signaling pathway hsa04340

Pathways related to Holoprosencephaly according to GeneCards Suite gene sharing:

(show all 15)
# Super pathways Score Top Affiliating Genes
1
Pathways in cancer 36
12.66 SHH PTCH1 GLI2 FGFR1 FGF8
2
Signaling by Hedgehog 65
Show member pathways
 12.39 SHH PTCH1 GLI2 GAS1 CDON
3
Mesodermal Commitment Pathway 1
Show member pathways
 12.22 ZIC2 NODAL GLI2 FOXH1 FGFR1 FGF8
4
Neural Crest Differentiation 1
11.73 ZIC1 FGFR1 FGF8
5
Neural Stem Cell Differentiation Pathways and Lineage-specific Markers 64
11.6 SHH FGFR1 FGF8
6
Differentiation Pathway 1
11.35 SHH NODAL FGF8
7
Heart Development 1
11.32 SHH FOXH1 FGF8
8
Hedgehog signaling events mediated by Gli proteins 1
11.25 SHH PTCH1 GLI2
9
Hedgehog signaling pathway (KEGG) 36
11.25 SHH PTCH1 GLI2 GAS1 CDON
10
Development_Hedgehog and PTH signaling pathways in bone and cartilage development 22
11.17 SHH PTCH1 GLI2
11
Dopaminergic Neurogenesis 1
11.02 SHH GLI2 FGF8
12
Hedgehog Signaling Pathway (WikiPathways) 1
Show member pathways
 10.78 SHH PTCH1 GLI2
13
Signaling events mediated by the Hedgehog family 1
Show member pathways
 10.5 SHH PTCH1 GLI2 GAS1 CDON
14
Glypican 3 network 1
10.41 SHH PTCH1
15
Tgif disruption of Shh signaling 1
10.21 TGIF1 SHH NODAL FGF8
Sources

GO Terms for Holoprosencephaly

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

(show top 50) (show all 58)
# Name GO ID Score Top Affiliating Genes
1 positive regulation of transcription by RNA polymerase II GO:0045944 10.21 ZIC1 SIX3 SHH NODAL GLI2 FOXH1
2 negative regulation of transcription by RNA polymerase II GO:0000122 10.13 TGIF1 SHH PTCH1 NODAL GLI2 FOXH1
3 positive regulation of transcription, DNA-templated GO:0045893 10.11 ZIC2 ZIC1 SHH PTCH1 GLI2 FOXH1
4 positive regulation of cell proliferation GO:0008284 10.1 SHH NODAL GLI2 FGFR1 FGF8
5 multicellular organism development GO:0007275 10.02 ZIC2 ZIC1 TGIF1 SIX3 SHH NODAL
6 heart development GO:0007507 9.99 SHH NODAL GLI2 FGF8
7 in utero embryonic development GO:0001701 9.98 PTCH1 NODAL GLI2 FGFR1
8 regulation of cell proliferation GO:0042127 9.93 SIX3 SHH PTCH1 FGFR1 DHCR7
9 kidney development GO:0001822 9.89 SHH GLI2 FGF8
10 positive regulation of neuron differentiation GO:0045666 9.88 GLI2 FGFR1 CDON
11 inner ear morphogenesis GO:0042472 9.85 ZIC1 FGFR1 FGF8
12 embryonic limb morphogenesis GO:0030326 9.83 SHH PTCH1 FGFR1
13 positive regulation of cell differentiation GO:0045597 9.82 SHH FGFR1 FGF8
14 smoothened signaling pathway GO:0007224 9.81 SHH PTCH1 GLI2 CDON
15 anatomical structure development GO:0048856 9.8 SIX3 SHH GLI2
16 branching involved in ureteric bud morphogenesis GO:0001658 9.8 SHH PTCH1 FGF8
17 heart looping GO:0001947 9.8 SHH NODAL FOXH1 FGF8
18 brain development GO:0007420 9.8 ZIC2 ZIC1 SIX3 PTCH1 NODAL FGFR1
19 cell fate commitment GO:0045165 9.76 SHH NODAL GAS1 FGF8
20 developmental growth GO:0048589 9.75 SHH GLI2 GAS1
21 regulation of smoothened signaling pathway GO:0008589 9.74 ZIC1 PTCH1 GAS1
22 embryonic pattern specification GO:0009880 9.73 SHH NODAL DISP1
23 pattern specification process GO:0007389 9.73 ZIC1 SHH PTCH1 GLI2
24 striated muscle cell differentiation GO:0051146 9.72 SHH CDON
25 embryonic heart tube development GO:0035050 9.72 NODAL FGF8
26 male genitalia development GO:0030539 9.72 SHH FGF8
27 osteoblast development GO:0002076 9.72 SHH GLI2
28 spinal cord motor neuron differentiation GO:0021522 9.72 SHH PTCH1 GLI2
29 pharyngeal system development GO:0060037 9.71 PTCH1 FGF8
30 somite development GO:0061053 9.71 SHH PTCH1
31 digestive tract morphogenesis GO:0048546 9.71 SHH NODAL
32 negative regulation of androgen receptor signaling pathway GO:0060766 9.71 NODAL FOXH1
33 aorta morphogenesis GO:0035909 9.71 FOXH1 FGF8
34 prostate gland development GO:0030850 9.7 SHH PTCH1
35 generation of neurons GO:0048699 9.7 FGFR1 FGF8
36 anatomical structure formation involved in morphogenesis GO:0048646 9.7 SHH NODAL GLI2
37 cell proliferation in forebrain GO:0021846 9.69 SIX3 FGF8
38 renal system development GO:0072001 9.69 SHH PTCH1
39 organ induction GO:0001759 9.68 FGFR1 FGF8
40 positive regulation of T cell differentiation in thymus GO:0033089 9.68 SHH GLI2
41 lung-associated mesenchyme development GO:0060484 9.68 SHH FGFR1
42 positive regulation of skeletal muscle tissue development GO:0048643 9.67 SHH CDON
43 smoothened signaling pathway involved in dorsal/ventral neural tube patterning GO:0060831 9.66 PTCH1 GLI2
44 telencephalon regionalization GO:0021978 9.66 SIX3 SHH
45 forebrain dorsal/ventral pattern formation GO:0021798 9.65 SIX3 FGF8
46 dorsal/ventral neural tube patterning GO:0021904 9.65 SHH PTCH1 GLI2
47 mammary gland duct morphogenesis GO:0060603 9.64 PTCH1 GLI2
48 spinal cord dorsal/ventral patterning GO:0021513 9.64 SHH GLI2
49 formation of anatomical boundary GO:0048859 9.62 SHH NODAL
50 smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation GO:0021938 9.61 SHH GLI2

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

# Name GO ID Score Top Affiliating Genes
1 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.8 ZIC2 ZIC1 TGIF1 SIX3 GLI2 FOXH1
2 DNA-binding transcription factor activity GO:0003700 9.73 ZIC2 ZIC1 TGIF1 SIX3 GLI2 FOXH1
3 co-SMAD binding GO:0070410 9.16 TGIF1 FOXH1
4 patched binding GO:0005113 8.96 SHH PTCH1
5 morphogen activity GO:0016015 8.62 SHH NODAL
Sources

Sources for Holoprosencephaly

About this section
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
The MalaCards human disease database index: 1-9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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