Details of Disease

General Information of Disease (ID: DIS4QVXO)

• Disease Name: Angelman syndrome
• Synonyms: happy puppet syndrome, formerly; AS; Angelman syndrome chromosome region; happy puppet syndrome (formerly); Angelman syndrome (Type 2); Angelman syndrome (Type 1); puppetlike syndrome; Angelman syndrome; happy puppet syndrome
• Disease Class: LD90: Intellectual development disorder
• Definition: A neurogenetic disorder characterized by severe intellectual deficit and distinct facial dysmorphic features.
• Disease Hierarchy:
  DIS6SVEE: Syndromic disease
  DISD715V: Hereditary neurological disease
  DIS4QVXO: Angelman syndrome
• ICD Code:
  ICD-11: ICD-11: LD90.0
  ICD-10: ICD-10: Q93.5
  Expand ICD-11: 'LD90.0
  Expand ICD-10: 'Q93.5
• Disease Identifiers:
  MONDO ID: MONDO_0007113
  MESH ID: D017204
  UMLS CUI: C0162635
  OMIM ID: 105830
  MedGen ID: 58144
  Orphanet ID: 72
  SNOMED CT ID: 76880004

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 5 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
OV101	DMA6LR3	Phase 3	NA	[1]
GTX-102	DMY87RJ	Phase 1/2	Antisense oligonucleotide	[2]
ION582	DMAEEFS	Phase 1/2	Antisense oligonucleotide	[3]
BIO-017	DMYHK3Y	Phase 1	NA	[4]
Rugonersen	DMYT0HY	Phase 1	Nucleic acid	[5]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 34 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
UBE3A	OTIA27P3	Definitive	Autosomal dominant	[6]
RNF2	OTFPLOIN	Limited	Biomarker	[17]
STOML3	OTLQGALK	Limited	Biomarker	[18]
NIPA1	OT9ODC8X	Disputed	Genetic Variation	[19]
PVALB	OTZW1WVQ	Disputed	Biomarker	[20]
HERC2	OTNQYKOB	moderate	Genetic Variation	[21]
CBLL2	OTB4AD3V	Strong	Genetic Variation	[22]
CDKL5	OTGL5HRV	Strong	Genetic Variation	[15]
GABRB3	OT80C3D4	Strong	Genetic Variation	[8]
HERC1	OT73FVYZ	Strong	Genetic Variation	[23]
MKRN3	OTAFO4YR	Strong	Genetic Variation	[24]
MUL1	OT2JC9YR	Strong	Genetic Variation	[22]
NPAS3	OT8D1ILB	Strong	Biomarker	[25]
OCA2	OTDWIGBF	Strong	Biomarker	[26]
PRKN	OTJBN41W	Strong	Genetic Variation	[22]
ATP8A1	OT2B7XBT	Definitive	Genetic Variation	[27]
CAMK2A	OTJGX19T	Definitive	Biomarker	[28]
CASK	OT8EF7ZF	Definitive	Genetic Variation	[15]
COPS2	OTDSCPVV	Definitive	Biomarker	[29]
CYFIP1	OTOBEH24	Definitive	Biomarker	[30]
DBI	OT884QY9	Definitive	Altered Expression	[31]
DERL1	OTJUS74N	Definitive	Genetic Variation	[32]
DYM	OTQ670WI	Definitive	Genetic Variation	[33]
EEF1E1	OTRA6XOB	Definitive	Biomarker	[12]
HAP1	OT6SG0JQ	Definitive	Biomarker	[34]
LAMTOR1	OTIBJBW9	Definitive	Biomarker	[12]
MAFK	OTZJUE4P	Definitive	Biomarker	[12]
NDN	OTYBYJ82	Definitive	Biomarker	[35]
NIPA2	OT4NEBNO	Definitive	Genetic Variation	[19]
NNAT	OTNRLO7G	Definitive	Biomarker	[20]
NPAP1	OTECLRPR	Definitive	Altered Expression	[36]
PSMD4	OTH1VZTM	Definitive	Genetic Variation	[37]
SCG5	OTXSJMT1	Definitive	Genetic Variation	[38]
TPPP2	OTI3WA6X	Definitive	Biomarker	[12]

This Disease Is Related to 9 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
GABRA5	TTNZPQ1	Limited	Biomarker	[7]
GABRG3	TTEX6LM	moderate	Genetic Variation	[8]
DYRK1A	TTSBVFO	Strong	Genetic Variation	[9]
MC1R	TT0MV2T	Strong	Altered Expression	[10]
PRNP	TTY5F9C	Strong	Biomarker	[11]
ATRAID	TTFLIKM	Definitive	Biomarker	[12]
EPHA6	TTFAHWI	Definitive	Biomarker	[13]
SLC5A7	TTRV7W3	Definitive	Biomarker	[13]
UBE3A	TTUZX6V	Definitive	Autosomal dominant	[6]

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
ATP10A	DTTQ8WI	Limited	Genetic Variation	[14]
SLC9A6	DTN0JXW	Strong	Genetic Variation	[15]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
CYP26B1	DEZT8FM	Definitive	Altered Expression	[16]

References

• [1] ClinicalTrials.gov (NCT03882918) An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals With Angelman Syndrome. U.S.National Institutes of Health.
• [2] ClinicalTrials.gov (NCT04259281) A Phase 1/2 Open-label, Multiple-dose, Dose-escalating Clinical Trial of the Safety and Tolerability of GTX-102 in Pediatric Patients With Angelman Syndrome (AS). U.S.National Institutes of Health.
• [3] ClinicalTrials.gov (NCT05127226) HALOS: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION582 in Patients With Angelman Syndrome. U.S.National Institutes of Health.
• [4] Clinical pipeline report, company report or official report of Biom Therapeutics
• [5] Clinical pipeline report, company report or official report of Roche
• [6] 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.
• [7] Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.Genomics. 2001 Sep;77(1-2):105-13. doi: 10.1006/geno.2001.6617.
• [8] Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.Biol Psychiatry. 2019 May 1;85(9):752-759. doi: 10.1016/j.biopsych.2019.01.008. Epub 2019 Jan 19.
• [9] DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.Eur J Hum Genet. 2015 Nov;23(11):1473-81. doi: 10.1038/ejhg.2015.71. Epub 2015 May 6.
• [10] UBE3A regulates MC1R expression: a link to hypopigmentation in Angelman syndrome.Pigment Cell Melanoma Res. 2011 Oct;24(5):944-52. doi: 10.1111/j.1755-148X.2011.00884.x. Epub 2011 Jul 27.
• [11] Parent-of-origin testing for 15q11-q13 gains by quantitative DNA methylation analysis.J Mol Diagn. 2012 May-Jun;14(3):192-8. doi: 10.1016/j.jmoldx.2012.01.005. Epub 2012 Mar 14.
• [12] UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity.Elife. 2018 Jul 18;7:e37993. doi: 10.7554/eLife.37993.
• [13] Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation.Eur J Hum Genet. 2010 Nov;18(11):1228-35. doi: 10.1038/ejhg.2010.95. Epub 2010 Jun 23.
• [14] False deletion of the D15S986 maternal allele in a suspected case of Angelman syndrome.Clin Chim Acta. 2015 Jan 15;439:191-4. doi: 10.1016/j.cca.2014.10.015. Epub 2014 Oct 30.
• [15] Genetic disorders associated with postnatal microcephaly.Am J Med Genet C Semin Med Genet. 2014 Jun;166C(2):140-55. doi: 10.1002/ajmg.c.31400. Epub 2014 May 16.
• [16] Loss of Angelman Syndrome Protein E6AP Disrupts a Novel Antagonistic Estrogen-Retinoic Acid Transcriptional Crosstalk in Neurons.Mol Neurobiol. 2018 Sep;55(9):7187-7200. doi: 10.1007/s12035-018-0871-9. Epub 2018 Jan 31.
• [17] Modulation of hippocampal synapse maturation by activity-regulated E3 ligase via non-canonical pathway.Neuroscience. 2017 Nov 19;364:226-241. doi: 10.1016/j.neuroscience.2017.08.057. Epub 2017 Sep 8.
• [18] Mechanisms of imprinting of the Prader-Willi/Angelman region.Am J Med Genet A. 2008 Aug 15;146A(16):2041-52. doi: 10.1002/ajmg.a.32364.
• [19] Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder.J Intellect Disabil Res. 2017 Jun;61(6):568-579. doi: 10.1111/jir.12382. Epub 2017 Apr 7.
• [20] Down-Regulation of miRNA-708 Promotes Aberrant Calcium Signaling by Targeting Neuronatin in a Mouse Model of Angelman Syndrome.Front Mol Neurosci. 2019 Feb 13;12:35. doi: 10.3389/fnmol.2019.00035. eCollection 2019.
• [21] The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination.Oncotarget. 2016 Aug 30;7(35):56083-56106. doi: 10.18632/oncotarget.11270.
• [22] A bipartite boundary element restricts UBE3A imprinting to mature neurons.Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2181-2186. doi: 10.1073/pnas.1815279116. Epub 2019 Jan 23.
• [23] A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder. Hum Mutat. 2012 Dec;33(12):1639-46. doi: 10.1002/humu.22237.
• [24] DNA methylation patterns in human tissues of uniparental origin using a zinc-finger gene (ZNF127) from the Angelman/Prader-Willi region.Am J Med Genet. 1996 Jan 11;61(2):140-6. doi: 10.1002/(SICI)1096-8628(19960111)61:2<140::AID-AJMG7>3.0.CO;2-0.
• [25] Neuronal PAS Domain Proteins 1 and 3 Are Master Regulators of Neuropsychiatric Risk Genes.Biol Psychiatry. 2017 Aug 1;82(3):213-223. doi: 10.1016/j.biopsych.2017.03.021. Epub 2017 Apr 6.
• [26] Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.Cell Rep. 2016 Dec 20;17(12):3115-3124. doi: 10.1016/j.celrep.2016.11.067.
• [27] A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome.Nat Genet. 2001 May;28(1):19-20. doi: 10.1038/ng0501-19.
• [28] Environmental Enrichment Improves Behavioral Abnormalities in a Mouse Model of Angelman Syndrome.Mol Neurobiol. 2017 Sep;54(7):5319-5326. doi: 10.1007/s12035-016-0080-3. Epub 2016 Sep 1.
• [29] Molecular characterisation of four cases of intrachromosomal triplication of chromosome 15q11-q14.J Med Genet. 2001 Jan;38(1):26-34. doi: 10.1136/jmg.38.1.26.
• [30] Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances.Eur J Med Genet. 2009 Mar-Jun;52(2-3):108-15. doi: 10.1016/j.ejmg.2009.03.010. Epub 2009 Mar 27.
• [31] Peripheral markers of the gamma-aminobutyric acid (GABA)ergic system in Angelman's syndrome.J Child Neurol. 2003 Jan;18(1):21-5. doi: 10.1177/08830738030180010801.
• [32] Girl with monosomy 1p36 and Angelman syndrome due to unbalanced der(1) transmission of a maternal translocation t(1;15)(p36.3;q13.1).Am J Med Genet A. 2004 Nov 15;131(1):94-8. doi: 10.1002/ajmg.a.30413.
• [33] Case report: Angelman syndrome in an individual with a small SMC(15) and paternal uniparental disomy: a case report with reference to the assessment of cognitive functioning and autistic symptomatology.J Autism Dev Disord. 2003 Apr;33(2):171-6. doi: 10.1023/a:1022991410822.
• [34] HAP1 is an in vivo UBE3A target that augments autophagy in a mouse model of Angelman syndrome.Neurobiol Dis. 2019 Dec;132:104585. doi: 10.1016/j.nbd.2019.104585. Epub 2019 Aug 21.
• [35] Physical mapping studies at D15S10: implications for candidate gene identification in the Angelman syndrome/Prader-Willi syndrome chromosome region of 15q11-q13.Genomics. 1994 Jan 1;19(1):170-2. doi: 10.1006/geno.1994.1031.
• [36] C15orf2 and a novel noncoding transcript from the Prader-Willi/Angelman syndrome region show monoallelic expression in fetal brain.Genomics. 2007 May;89(5):588-95. doi: 10.1016/j.ygeno.2006.12.008. Epub 2007 Mar 6.
• [37] Angelman syndrome-associated point mutations in the Zn(2+)-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome.J Biol Chem. 2018 Nov 23;293(47):18387-18399. doi: 10.1074/jbc.RA118.004653. Epub 2018 Sep 26.
• [38] Assignment of the gene for neuroendocrine protein 7B2 (SGNE1 locus) to mouse chromosome region 2[E3-F3] and to human chromosome region 15q11-q15.Genomics. 1990 Mar;6(3):436-40. doi: 10.1016/0888-7543(90)90473-8.