Details of Disease

General Information of Disease (ID: DISR35EC)

Disease Name Holoprosencephaly
Synonyms HPE; holoprosencephaly sequence
Definition
Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and 28th day of gestation, and affecting both the forebrain and face, which results in neurological manifestations and facial anomalies of variable severity.
Disease Hierarchy
DISC4U0P: Non-acquired combined pituitary hormone deficiency
DIS6SVEE: Syndromic disease
DIS2BIP8: Congenital nervous system disorder
DISD715V: Hereditary neurological disease
DISDOXWZ: Multiple congenital anomalies/dysmorphic syndrome-intellectual disability
DISR35EC: Holoprosencephaly
Disease Identifiers
MONDO ID
MONDO_0016296
MESH ID
D016142
UMLS CUI
C0079541
MedGen ID
38214
HPO ID
HP:0001360
Orphanet ID
2162
SNOMED CT ID
30915001

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)
This Disease Is Related to 34 DOT Molecule(s)
Gene Name DOT ID Evidence Level Mode of Inheritance REF
ZIC2 OTZ97UI5 Supportive Autosomal recessive [1]
CDON OT81X593 Limited Biomarker [12]
FOXH1 OTEXJ9SL Limited Biomarker [3]
GAS1 OTKJXG52 Limited Autosomal dominant [13]
GLI3 OTKDOE94 Limited Genetic Variation [14]
PTCH1 OTMG07H5 Limited Autosomal dominant [15]
MOGS OT99MBGB Disputed Genetic Variation [16]
SIM2 OT0QWHK4 Disputed Biomarker [17]
DISP1 OTLDFZSY Supportive Autosomal recessive [1]
FGF8 OTFU0IUW Supportive Autosomal recessive [1]
FGFR1 OT4GLCXW Supportive Autosomal recessive [1]
GLI2 OTIRV97L Supportive Autosomal recessive [1]
SHH OTOG2BXF Supportive Autosomal recessive [1]
SIX3 OTP5E3VU Supportive Autosomal recessive [1]
STIL OT9799VN Supportive Autosomal recessive [1]
CPLANE1 OTXGGNNB Strong Genetic Variation [5]
FBXW11 OT2A6RLR Strong Biomarker [18]
MNX1 OTXP9FH1 Strong Altered Expression [19]
NOG OTGRHHPG Strong Genetic Variation [20]
PPP1R12A OT4AVU95 Strong Biomarker [21]
RFX4 OTYFRHPA Strong Biomarker [22]
TGIF1 OTN9VHAG Strong Biomarker [23]
TGIF2 OTMKKE3W Strong Biomarker [24]
BOC OTXBCY9W Definitive Genetic Variation [25]
CHRD OTNM60Y1 Definitive Genetic Variation [26]
EAPP OTDPUE6Y Definitive Biomarker [27]
EYA4 OTINGR3Z Definitive Biomarker [28]
KATNB1 OT7CLZKS Definitive Genetic Variation [29]
OSCP1 OTZ4IFGJ Definitive Genetic Variation [30]
RALGAPA1 OTHT5DW0 Definitive Biomarker [31]
SMC1A OT9ZMRK9 Definitive Altered Expression [32]
STAG2 OTR6X1Q7 Definitive Altered Expression [32]
TCTN1 OTG5KEV8 Definitive Genetic Variation [33]
TCTN3 OTZSHERV Definitive Genetic Variation [33]
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⏷ Show the Full List of 34 DOT(s)
This Disease Is Related to 13 DTT Molecule(s)
Gene Name DTT ID Evidence Level Mode of Inheritance REF
DLL1 TT9CFQD Limited Biomarker [2]
NODAL TTK2O1Q Limited Biomarker [3]
RAC3 TT9BQ50 Limited Genetic Variation [4]
FGF8 TTIUF3J Supportive Autosomal recessive [1]
FGFR1 TTRLW2X Supportive Autosomal recessive [1]
GLI2 TT045OH Supportive Autosomal recessive [1]
SHH TTIENCJ Supportive Autosomal recessive [1]
SHH TTIENCJ moderate Genetic Variation [5]
TDGF1 TTN7HMG moderate Biomarker [6]
FGF8 TTIUF3J Strong Genetic Variation [7]
GLI2 TT045OH Strong Genetic Variation [8]
LRP2 TTPH1AJ Strong Altered Expression [9]
PLTP TTZF6SN Definitive Altered Expression [10]
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⏷ Show the Full List of 13 DTT(s)
This Disease Is Related to 1 DME Molecule(s)
Gene Name DME ID Evidence Level Mode of Inheritance REF
DHCR7 DEL7GFA Strong Genetic Variation [11]
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References

1 Recent advances in understanding inheritance of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):258-269. doi: 10.1002/ajmg.c.31619. Epub 2018 May 22.
2 NOTCH, a new signaling pathway implicated in holoprosencephaly.Hum Mol Genet. 2011 Mar 15;20(6):1122-31. doi: 10.1093/hmg/ddq556. Epub 2010 Dec 31.
3 Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway.Hum Mutat. 2016 Dec;37(12):1329-1339. doi: 10.1002/humu.23038. Epub 2016 Aug 23.
4 A de novo variant in RAC3 causes severe global developmental delay and a middle interhemispheric variant of holoprosencephaly.J Hum Genet. 2019 Nov;64(11):1127-1132. doi: 10.1038/s10038-019-0656-7. Epub 2019 Aug 16.
5 Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling.Eur J Hum Genet. 2018 Feb;26(2):197-209. doi: 10.1038/s41431-017-0019-9. Epub 2018 Jan 10.
6 A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects.Hum Genet. 2002 May;110(5):422-8. doi: 10.1007/s00439-002-0709-3. Epub 2002 Apr 10.
7 Loss-of-function mutations in FGF8 can be independent risk factors for holoprosencephaly.Hum Mol Genet. 2018 Jun 1;27(11):1989-1998. doi: 10.1093/hmg/ddy106.
8 Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization.Clin Endocrinol (Oxf). 2019 Mar;90(3):449-456. doi: 10.1111/cen.13914. Epub 2019 Jan 7.
9 Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE.Hum Genet. 2010 Apr;127(4):421-40. doi: 10.1007/s00439-009-0778-7.
10 Phospholipid transfer protein in the placental endothelium is affected by gestational diabetes mellitus.J Clin Endocrinol Metab. 2012 Feb;97(2):437-45. doi: 10.1210/jc.2011-1942. Epub 2011 Nov 16.
11 A novel mutation of the human 7-dehydrocholesterol reductase gene reduces enzyme activity in patients with holoprosencephaly.Biochem Biophys Res Commun. 2004 Feb 27;315(1):219-23. doi: 10.1016/j.bbrc.2004.01.041.
12 Homozygous variants in MAPRE2 and CDON in individual with skin folds, growth delay, retinal coloboma, and pyloric stenosis.Am J Med Genet A. 2019 Dec;179(12):2454-2458. doi: 10.1002/ajmg.a.61355. Epub 2019 Sep 9.
13 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
14 Genetic and Molecular Analyses indicate independent effects of TGIFs on Nodal and Gli3 in neural tube patterning.Eur J Hum Genet. 2017 Feb;25(2):208-215. doi: 10.1038/ejhg.2016.164. Epub 2016 Dec 7.
15 Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet. 2002 Apr;110(4):297-301. doi: 10.1007/s00439-002-0695-5. Epub 2002 Mar 2.
16 Prenatal diagnosis of holoprosencephaly in two fetuses with der (7)t(1;7)(q32;q32)pat inherited from the father with double translocations.Prenat Diagn. 2003 Feb;23(2):134-7. doi: 10.1002/pd.552.
17 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.Am J Hum Genet. 1995 Nov;57(5):1074-9.
18 Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1.J Hum Genet. 2006;51(8):721-726. doi: 10.1007/s10038-006-0010-8. Epub 2006 Jul 25.
19 Minimal clinical expression of the holoprosencephaly spectrum and of Currarino syndrome due to different cytogenetic rearrangements deleting the Sonic Hedgehog gene and the HLXB9 gene at 7q36.3.Am J Med Genet A. 2004 Jul 1;128A(1):85-92. doi: 10.1002/ajmg.a.30031.
20 Molecular analysis of the Noggin (NOG) gene in holoprosencephaly patients.Mol Genet Metab. 2012 Jun;106(2):241-3. doi: 10.1016/j.ymgme.2012.03.008. Epub 2012 Mar 21.
21 Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations. Am J Hum Genet. 2020 Jan 2;106(1):121-128. doi: 10.1016/j.ajhg.2019.12.004. Epub 2019 Dec 26.
22 Conditional ablation of the RFX4 isoform 1 transcription factor: Allele dosage effects on brain phenotype.PLoS One. 2018 Jan 3;13(1):e0190561. doi: 10.1371/journal.pone.0190561. eCollection 2018.
23 In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics.Genet Med. 2018 Jan;20(1):14-23. doi: 10.1038/gim.2017.68. Epub 2017 Jun 22.
24 Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l.Mol Cell Biol. 2017 Feb 15;37(5):e00527-16. doi: 10.1128/MCB.00527-16. Print 2017 Mar 1.
25 BOC is a modifier gene in holoprosencephaly.Hum Mutat. 2017 Nov;38(11):1464-1470. doi: 10.1002/humu.23286. Epub 2017 Jul 21.
26 Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly.Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):43-51. doi: 10.1002/ajmg.c.30256.
27 Defining a holoprosencephaly locus on human chromosome 14q13 and characterization of potential candidate genes.Genomics. 2005 May;85(5):608-21. doi: 10.1016/j.ygeno.2005.01.010.
28 EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts with SIX3 both physically and functionally.Hum Mutat. 2009 Oct;30(10):E946-55. doi: 10.1002/humu.21094.
29 Katanin p80 regulates human cortical development by limiting centriole and cilia number.Neuron. 2014 Dec 17;84(6):1240-57. doi: 10.1016/j.neuron.2014.12.017.
30 Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1.Hum Mutat. 2004 Dec;24(6):502-8. doi: 10.1002/humu.20102.
31 14q13.1-21.1 deletion encompassing the HPE8 locus in an adolescent with intellectual disability and bilateral microphthalmia, but without holoprosencephaly.Am J Med Genet A. 2012 Jun;158A(6):1427-33. doi: 10.1002/ajmg.a.35334. Epub 2012 May 11.
32 Cohesin complex-associated holoprosencephaly.Brain. 2019 Sep 1;142(9):2631-2643. doi: 10.1093/brain/awz210.
33 Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse.Dev Biol. 2017 Oct 1;430(1):156-165. doi: 10.1016/j.ydbio.2017.08.003. Epub 2017 Aug 8.