2011 Group Project 7 - Revision history

S8600021 at 01:08, 19 October 2011

2011-10-19T01:08:04Z

← Older revision		Revision as of 11:08, 19 October 2011
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			{{2011ProjectsMH}}
	='''Angelman Syndrome'''=		='''Angelman Syndrome'''=

S8600021: Protected "2011 Group Project 7": Protect from student change ([edit=sysop] (indefinite) [move=sysop] (indefinite))

2011-10-13T06:29:21Z

Protected "2011 Group Project 7": Protect from student change ([edit=sysop] (indefinite) [move=sysop] (indefinite))

← Older revision	Revision as of 16:29, 13 October 2011
(No difference)

Z3291643: /* Pathogenesis */

2011-10-13T02:24:04Z

Pathogenesis

← Older revision		Revision as of 12:24, 13 October 2011
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	'''Normal gene product: E6-AP ubiquitin ligase'''		'''Normal gene product: E6-AP ubiquitin ligase'''

	The function of UBE3A is to encode for [[#Glossary \| '''E6-AP''']] ubiquitin ligase, however its function in the development of the nervous system and the process of UBE3A mutation leading to cognitive impairment in AS patients is still vague.<ref name="PMID:20211139><pubmed>20211139</pubmed></ref> Past and current research has elucidated that E6-AP ubiquitin ligase is involved in the degradation of four proteins, listed below. Currently no protein with a direct role in [[#Glossary \| '''long-term potentiation (LTP)''']] as a target of E6-AP has been identified.<ref><pubmed>12684449</pubmed></ref> The identification of such target proteins would be a landmark discovery in further understanding of the pathogenesis, aetiology and prospective treatment strategies of AS, as LTP defects is one of the major neurological impairments of AS.		The function of UBE3A is to encode for [[#Glossary \| '''E6-AP''']] ubiquitin ligase, however its function in the development of the nervous system and the process of UBE3A mutation leading to cognitive impairment in AS patients is still vague.<ref name="PMID:20211139"><pubmed>20211139</pubmed></ref> Past and current research has elucidated that E6-AP ubiquitin ligase is involved in the degradation of four proteins, listed below. Currently no protein with a direct role in [[#Glossary \| '''long-term potentiation (LTP)''']] as a target of E6-AP has been identified.<ref><pubmed>12684449</pubmed></ref> The identification of such target proteins would be a landmark discovery in further understanding of the pathogenesis, aetiology and prospective treatment strategies of AS, as LTP defects is one of the major neurological impairments of AS.

	* p53 tumor suppressor protein		* p53 tumor suppressor protein

Z3291643: /* History */

2011-10-13T02:21:14Z

History

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	\|-bgcolor="mistyrose"		\|-bgcolor="mistyrose"
	\|'''2010'''		\|'''2010'''
	\|Protein named Arc identified as a target of AS gene product; UBE3A.<ref><pubmed>20211139</pubmed></ref>		\|Protein named Arc identified as a target of AS gene product; UBE3A.<ref name="PMID:20211139"><pubmed>20211139</pubmed></ref>
	\|-style="width:100%"		\|-style="width:100%"
	\|-bgcolor="mistyrose"		\|-bgcolor="mistyrose"

Z3291643: /* Genetic Counselling */

2011-10-13T02:17:40Z

Genetic Counselling

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	'''IIIc''': Individuals who are mosaic for the imprinting defect have less than 1% risk to siblings		'''IIIc''': Individuals who are mosaic for the imprinting defect have less than 1% risk to siblings

	'''IV''': UBE3A mutation can be either inherited or de novo mutation. If the mother is a carrier for this genetic mutation, the risk to siblings is up to 50% <ref><pubmed>11258627></ref>		'''IV''': UBE3A mutation can be either inherited or de novo mutation. If the mother is a carrier for this genetic mutation, the risk to siblings is up to 50% <ref><pubmed>11258627</pubmed></ref>

	'''V''': Individuals who present with AS clinically, but have no known underlying mechanism have an unknown risk to siblings.		'''V''': Individuals who present with AS clinically, but have no known underlying mechanism have an unknown risk to siblings.

Z3291643: /* History */

2011-10-13T02:15:16Z

History

← Older revision		Revision as of 12:15, 13 October 2011
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	In 1997, UBE3A gene was isolated by Dr. Joseph Wagstaff and Dr. Arthur Beaudet as the cause of Angelman Syndrome.<ref name="PMID20981772" /> The discovery of this [[#Glossary \| '''gene''']] led to the subsequent development of animal models and research aimed at finding a causal link between UBE3A gene abnormalities and characteristic features observed in Angelman Syndrome.		In 1997, UBE3A gene was isolated by Dr. Joseph Wagstaff and Dr. Arthur Beaudet as the cause of Angelman Syndrome.<ref name="PMID20981772" /> The discovery of this [[#Glossary \| '''gene''']] led to the subsequent development of animal models and research aimed at finding a causal link between UBE3A gene abnormalities and characteristic features observed in Angelman Syndrome.

	Currently, four different genetic abnormalities for Angelman Syndrome have been confirmed by genetic testing. They include: Deletion, [[#Glossary \| '''Uniparental Disomy''']] (UPD), [[#Glossary \| '''Imprinting''']] and UBE3A mutation.<ref name="~~PMID20211139~~" />		Currently, four different genetic abnormalities for Angelman Syndrome have been confirmed by genetic testing. They include: Deletion, [[#Glossary \| '''Uniparental Disomy''']] (UPD), [[#Glossary \| '''Imprinting''']] and UBE3A mutation.<ref name="PMID:20211139"><pubmed>20211139</pubmed></ref>

	Below is a timeline, summarising the key discoveries and advancements of the Angelman Syndrome:		Below is a timeline, summarising the key discoveries and advancements of the Angelman Syndrome:

Z3291622: /* History */

2011-10-13T02:10:43Z

History

← Older revision		Revision as of 12:10, 13 October 2011
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	In 1997, UBE3A gene was isolated by Dr. Joseph Wagstaff and Dr. Arthur Beaudet as the cause of Angelman Syndrome.<ref name="PMID20981772" /> The discovery of this [[#Glossary \| '''gene''']] led to the subsequent development of animal models and research aimed at finding a causal link between UBE3A gene abnormalities and characteristic features observed in Angelman Syndrome.		In 1997, UBE3A gene was isolated by Dr. Joseph Wagstaff and Dr. Arthur Beaudet as the cause of Angelman Syndrome.<ref name="PMID20981772" /> The discovery of this [[#Glossary \| '''gene''']] led to the subsequent development of animal models and research aimed at finding a causal link between UBE3A gene abnormalities and characteristic features observed in Angelman Syndrome.

	Currently, four different genetic abnormalities for Angelman Syndrome have been confirmed by genetic testing. They include: Deletion, [[#Glossary \| '''Uniparental Disomy''']] (UPD), [[#Glossary \| '''Imprinting''']] and UBE3A mutation.<ref name="PMID20211139"/>		Currently, four different genetic abnormalities for Angelman Syndrome have been confirmed by genetic testing. They include: Deletion, [[#Glossary \| '''Uniparental Disomy''']] (UPD), [[#Glossary \| '''Imprinting''']] and UBE3A mutation.<ref name="PMID20211139" />

	Below is a timeline, summarising the key discoveries and advancements of the Angelman Syndrome:		Below is a timeline, summarising the key discoveries and advancements of the Angelman Syndrome:

Z3291622: /* Diagnosis */

2011-10-13T02:08:13Z

Diagnosis

← Older revision		Revision as of 12:08, 13 October 2011
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	[[File:Angelman Syndrome Prenatal Diagnosis.jpg\|thumb\|250px\|right\|Flowchart of AS Diagnosis.]]		[[File:Angelman Syndrome Prenatal Diagnosis.jpg\|thumb\|250px\|right\|Flowchart of AS Diagnosis.]]

	Prenatal detection of deletions of 15q11.2-q13, [[#Glossary \| '''Paternal UPD''']] (~~[[#Glossary \| '''~~Uniparental Disomy~~''']]~~), Imprinting defects and UBE3A mutations are done through DNA/chromosome/FISH analysis of fetal cells obtained by either [[#Glossary \| '''Chorionic Villus Sampling''']](CVS) or [[#Glossary \| '''Amniocentesis''']].<ref name="PMID20445456"/>		Prenatal detection of deletions of 15q11.2-q13, [[#Glossary \| '''Paternal UPD''']] (Uniparental Disomy), Imprinting defects and UBE3A mutations are done through DNA/chromosome/FISH analysis of fetal cells obtained by either [[#Glossary \| '''Chorionic Villus Sampling''']](CVS) or [[#Glossary \| '''Amniocentesis''']].<ref name="PMID20445456"/>
	DNA methylation analysis using [[#Glossary \| '''Amniocytes''']] is usually the first test carried out in molecular diagnosis of AS.<ref name="PMID18059071"><pubmed>18059071</pubmed></ref> An abnormal result is followed up by either a FISH or array CGH analysis to search for a deletion on chromosome 15. If they produce a normal result, then UPD testing using DNA polymorphysims is carried out. If there is no evidence of UPD, other DNA analysis tests are used search for an imprinting centre deletion.<ref name="PMID9792887"><pubmed>9792887</pubmed></ref> A normal DNA methylation analysis is followed by a UBE3A sequence analysis.<ref name="PMID18059071"/> In addition, a parent of origin test is also done to determine if the genetic disruption is of maternal origin or paternal origin. If it is maternally derived the fetus is diagnosed with AS (a paternally derived genetic disruption is indicative of Prader-Willi Syndrome).<ref name="PMID17020468"><pubmed>17020468</pubmed></ref>		DNA methylation analysis using [[#Glossary \| '''Amniocytes''']] is usually the first test carried out in molecular diagnosis of AS.<ref name="PMID18059071"><pubmed>18059071</pubmed></ref> An abnormal result is followed up by either a FISH or array CGH analysis to search for a deletion on chromosome 15. If they produce a normal result, then UPD testing using DNA polymorphysims is carried out. If there is no evidence of UPD, other DNA analysis tests are used search for an imprinting centre deletion.<ref name="PMID9792887"><pubmed>9792887</pubmed></ref> A normal DNA methylation analysis is followed by a UBE3A sequence analysis.<ref name="PMID18059071"/> In addition, a parent of origin test is also done to determine if the genetic disruption is of maternal origin or paternal origin. If it is maternally derived the fetus is diagnosed with AS (a paternally derived genetic disruption is indicative of Prader-Willi Syndrome).<ref name="PMID17020468"><pubmed>17020468</pubmed></ref>

Z3291643: /* Pathogenesis */

2011-10-13T00:00:45Z

Pathogenesis

← Older revision		Revision as of 10:00, 13 October 2011
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	'''Regional functioning of UBE3A'''		'''Regional functioning of UBE3A'''

	Despite the uncertain progression of UBE3A mutation and the neurological abnormalities characteristic of AS, animal models have illustrated the vital role of UBE3A in the normal functioning of the brain. This can be exemplified by a study which utilized a mouse model with target inactivation of the gene UBE3A resulting in the manifestation of classical features of AS.<ref><pubmed>11895368</pubmed></ref> In addition, the fact that imprinting of UBE3A takes place only in specific brain regions ([[#Glossary \| '''cerebellum''']] , [[#Glossary \| '''olfactory tracts''']] and the [[#Glossary \| '''hippocampus''']]) confirms the hypothesis that the loss of this gene would be detrimental in cognitive development.<ref><pubmed>20398390</pubmed></ref> Most genes are inherited in copies of two, one paternal and the other maternal; however, some genes, such as UBE3A only have one functional copy as the other is silenced, coined 'imprinting'. Imprinting of the paternal copy of UBE3A takes place in some cell populations, such as the hippocampal [[#Glossary \| '''neurons''']]and [[#Glossary \| '''Purkinje cells''']] ~~Purkinje cells~~ in the cerebellum.<ref><pubmed>9288101</pubmed></ref> This means only the maternal UBE3A is functionally expressed in these particular brain regions. Thus a [[#Glossary \| '''de novo mutation''']] in the maternal copy of the gene will result in the complete absence of functional E6-AP in the associated brain areas.<ref><pubmed>9288088</pubmed></ref>		Despite the uncertain progression of UBE3A mutation and the neurological abnormalities characteristic of AS, animal models have illustrated the vital role of UBE3A in the normal functioning of the brain. This can be exemplified by a study which utilized a mouse model with target inactivation of the gene UBE3A resulting in the manifestation of classical features of AS.<ref><pubmed>11895368</pubmed></ref> In addition, the fact that imprinting of UBE3A takes place only in specific brain regions ([[#Glossary \| '''cerebellum''']] , [[#Glossary \| '''olfactory tracts''']] and the [[#Glossary \| '''hippocampus''']]) confirms the hypothesis that the loss of this gene would be detrimental in cognitive development.<ref><pubmed>20398390</pubmed></ref> Most genes are inherited in copies of two, one paternal and the other maternal; however, some genes, such as UBE3A only have one functional copy as the other is silenced, coined 'imprinting'. Imprinting of the paternal copy of UBE3A takes place in some cell populations, such as the hippocampal [[#Glossary \| '''neurons''']] and [[#Glossary \| '''Purkinje cells''']] in the cerebellum.<ref><pubmed>9288101</pubmed></ref> This means only the maternal UBE3A is functionally expressed in these particular brain regions. Thus a [[#Glossary \| '''de novo mutation''']] in the maternal copy of the gene will result in the complete absence of functional E6-AP in the associated brain areas.<ref><pubmed>9288088</pubmed></ref>

	It is also known that UBE3A plays an important role in synaptic transmission, but exactly how it does so is still not completely understood.<ref name="PMID:9808466"><pubmed>9808466</pubmed></ref>		It is also known that UBE3A plays an important role in synaptic transmission, but exactly how it does so is still not completely understood.<ref name="PMID:9808466"><pubmed>9808466</pubmed></ref>
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	Absence of UBE3A in mice manifest similar phenotype to human AS, as illustrated by motor and learning deficits with inducible seizures.<ref><pubmed>21235769</pubmed></ref> It has been shown through various mice model studies that larger deletions, ie. from UBE3A to GABRB3, more closely mirrors the large 6Mb deletions seen in human AS patients. Numerous tests, such as the Rotarod (for motor coordination and learning ability), Morris water maze test (for spatial learning and memory) and [[#Glossary \| '''EEG''']] (electroencephalography), were carried out on UBE3A null mutants, which showed the results to be abnormal or impaired.<ref><pubmed>20808828</pubmed></ref> Other studies using mouse models have also outlined the obesity observed in 15% of AS children, albeit it is not the major characterisitics of AS.<ref><pubmed>17259980</pubmed></ref> The diagram on the right clearly highlights the results obtained from such mouse model studies of AS, where the absence of UBE3A accumulated in deficits of motor function and obesity. In addition, excessive drooling and feeding difficulties were also highlighted by mice models with inactivated UBE3A, reflected by defects in fluid consumption and licking.<ref><pubmed>18413322</pubmed></ref>		Absence of UBE3A in mice manifest similar phenotype to human AS, as illustrated by motor and learning deficits with inducible seizures.<ref><pubmed>21235769</pubmed></ref> It has been shown through various mice model studies that larger deletions, ie. from UBE3A to GABRB3, more closely mirrors the large 6Mb deletions seen in human AS patients. Numerous tests, such as the Rotarod (for motor coordination and learning ability), Morris water maze test (for spatial learning and memory) and [[#Glossary \| '''EEG''']] (electroencephalography), were carried out on UBE3A null mutants, which showed the results to be abnormal or impaired.<ref><pubmed>20808828</pubmed></ref> Other studies using mouse models have also outlined the obesity observed in 15% of AS children, albeit it is not the major characterisitics of AS.<ref><pubmed>17259980</pubmed></ref> The diagram on the right clearly highlights the results obtained from such mouse model studies of AS, where the absence of UBE3A accumulated in deficits of motor function and obesity. In addition, excessive drooling and feeding difficulties were also highlighted by mice models with inactivated UBE3A, reflected by defects in fluid consumption and licking.<ref><pubmed>18413322</pubmed></ref>



	~~===Pathophysiology===~~

	~~'''Cognitive defects'''~~

	~~[[File:Role of UBE3A in dendritic spine neuronal synapses.png\|thumb\|250px\|right\|Role of UBE3A in dendritic spine neuronal synapses.]]~~

	AS patients present with abnormally high UBE3A, leading to neurological impairment. Recent identification of key target proteins of Ephexin-58 (Eph-5) and Arc (Activity-Regulated Cytoskeleton-associated protein) have aided in better understanding of the progression of UBE3A to cognitive defects. These two proteins are vital in the understanding of AS as Eph-5 determines synapse numbers and Arc contributes to plasticity and synapse function.<ref><pubmed>21164477</pubmed></ref> Studies utilizing mice models have illustrated that UBE3A null mice could not ubiquitinate Eph-5, thus increasing its levels and limiting the growth of dendritic spines by the activation of RhoA. This subsequent activation of RhoA inhibits synapse formation and results in neuronal defects.

	In contrast, mice with normally functioning UBE3A showed phosphorylated Eph-5, resulting from the interaction of two neurons via the activation of EphB signalling receptor.<ref><pubmed>21029865</pubmed></ref> Phosphorylation of Eph-5 allows UBE3A to ubiquitinate and degrade it. This degradation of Eph-5 permits new synaptic connections to form with cells they come into contact with. However, in AS, the absence of UBE3A means Eph-5 cannot be degraded, so RhoA activity is prolonged to reduce synaptic formation.

	As mentioned previously, Arc plays a pivitol role in synapse function as it removes synaptic receptors that respond to glutamate, a [[#Glossary \| '''neurotransmitter''']].<ref><pubmed>17088211</pubmed></ref> In UBE3A present neurons, UBE3A ubiquitinates Arc, leading to it degradation as illustrated by the diagram on the left. However, in UBE3A deficient neurons, Arc accumulates and prevents the proper synaptic communications essential for normal cognitive functions.<ref name="PMID20211139"><pubmed>20211139</pubmed></ref>

	==Signs and Symptoms==		==Signs and Symptoms==

Z3291643: /* Glossary */

2011-10-12T23:59:10Z

Glossary

← Older revision		Revision as of 09:59, 13 October 2011
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	'''betaine''': Also known as betaine anhydrous or trimethylglycine (TMG), assists the body in metabolising the amino acid, homocysteine. Can be consumed via beets, broccoli, grains, shellfish, and spinach.		'''betaine''': Also known as betaine anhydrous or trimethylglycine (TMG), assists the body in metabolising the amino acid, homocysteine. Can be consumed via beets, broccoli, grains, shellfish, and spinach.

			'''cerebellum''': Region of the brain that plays an important role in motor control. It is also involved in some cognitive functions such as attention and language.

	'''Chorionic Villus Sampling''': A prenatal diagnostic test used to detect chromosomal abnormalities in the developing fetus by extracting and testing chorionic villus (placental tissue).		'''Chorionic Villus Sampling''': A prenatal diagnostic test used to detect chromosomal abnormalities in the developing fetus by extracting and testing chorionic villus (placental tissue).
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	'''gene''': A molecular unit of heredity of a living organism.		'''gene''': A molecular unit of heredity of a living organism.

			'''hippocampus''': Area buried deep in the forebrain that helps regulate emotion and memory

	'''hyperphagia''': (Also referred to as Polyphagia) Excessive ingestion of food beyond the dietary and energy requirements of the body.		'''hyperphagia''': (Also referred to as Polyphagia) Excessive ingestion of food beyond the dietary and energy requirements of the body.
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	'''neurogenetic''': Genetic basis of the nervous system.		'''neurogenetic''': Genetic basis of the nervous system.

			'''neuron''': Cells of the nervous system that can be electrically excited to transmit information by electrical and chemical signaling

	'''neurotransmitter''': Transmits neuronal signals to a target cell. They are first packaged in vesicles just beneath the membrane of presynaptic axon terminals and released into the synaptic cleft (space between the two interacting neurons) and enter the postsynaptic dendrite.		'''neurotransmitter''': Transmits neuronal signals to a target cell. They are first packaged in vesicles just beneath the membrane of presynaptic axon terminals and released into the synaptic cleft (space between the two interacting neurons) and enter the postsynaptic dendrite.
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	'''oesophagus reflux''': Impairment of a sphincter in the lower end of the oesophagus leads to the back flow of stomach acid into the oesophagus. Heartburn is a typical symptom.		'''oesophagus reflux''': Impairment of a sphincter in the lower end of the oesophagus leads to the back flow of stomach acid into the oesophagus. Heartburn is a typical symptom.

			'''olfactory tract''': It is a pathway for the sense of smell containing axons from some of the neurons in the olfactory bulb.

	'''paediatrician''': Physicians that specialise on infants, children and adolescents.		'''paediatrician''': Physicians that specialise on infants, children and adolescents.
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	'''Proband''': Is the person (or animal) being studied or reported on in a genetic investigation. Most commonly it refers to the first affected family member who requires medical help for a genetic disorder.		'''Proband''': Is the person (or animal) being studied or reported on in a genetic investigation. Most commonly it refers to the first affected family member who requires medical help for a genetic disorder.

			'''Purkinje cells''': Large neuron with many branching extensions that is found in the cortex of the cerebellum of the brain and plays a fundamental role in controlling motor movement

	'''Robertsonian translocation''': Rearrangement of the chromosome, occurs in 5 chromosome including 13,14,15,21 and 22. This type of mutation occurs in chromosomes with the centromere not at the centre, resulting in long and short arm chromosomes. Translocation breaks the chromosome at the centromere so the long arm attaches to the other long arm, and the same for the short arm happens. Cell division will result in the loss of the short arms as they do not contain important genes.		'''Robertsonian translocation''': Rearrangement of the chromosome, occurs in 5 chromosome including 13,14,15,21 and 22. This type of mutation occurs in chromosomes with the centromere not at the centre, resulting in long and short arm chromosomes. Translocation breaks the chromosome at the centromere so the long arm attaches to the other long arm, and the same for the short arm happens. Cell division will result in the loss of the short arms as they do not contain important genes.

← Older revision		Revision as of 12:08, 13 October 2011
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	[[File:Angelman Syndrome Prenatal Diagnosis.jpg\|thumb\|250px\|right\|Flowchart of AS Diagnosis.]]		[[File:Angelman Syndrome Prenatal Diagnosis.jpg\|thumb\|250px\|right\|Flowchart of AS Diagnosis.]]

	Prenatal detection of deletions of 15q11.2-q13, [[#Glossary \| '''Paternal UPD''']] (~~[[#Glossary \| '''~~Uniparental Disomy~~''']]~~), Imprinting defects and UBE3A mutations are done through DNA/chromosome/FISH analysis of fetal cells obtained by either [[#Glossary \| '''Chorionic Villus Sampling''']](CVS) or [[#Glossary \| '''Amniocentesis''']].<ref name="PMID20445456"/>		Prenatal detection of deletions of 15q11.2-q13, [[#Glossary \| '''Paternal UPD''']] (Uniparental Disomy), Imprinting defects and UBE3A mutations are done through DNA/chromosome/FISH analysis of fetal cells obtained by either [[#Glossary \| '''Chorionic Villus Sampling''']](CVS) or [[#Glossary \| '''Amniocentesis''']].<ref name="PMID20445456"/>
	DNA methylation analysis using [[#Glossary \| '''Amniocytes''']] is usually the first test carried out in molecular diagnosis of AS.<ref name="PMID18059071"><pubmed>18059071</pubmed></ref> An abnormal result is followed up by either a FISH or array CGH analysis to search for a deletion on chromosome 15. If they produce a normal result, then UPD testing using DNA polymorphysims is carried out. If there is no evidence of UPD, other DNA analysis tests are used search for an imprinting centre deletion.<ref name="PMID9792887"><pubmed>9792887</pubmed></ref> A normal DNA methylation analysis is followed by a UBE3A sequence analysis.<ref name="PMID18059071"/> In addition, a parent of origin test is also done to determine if the genetic disruption is of maternal origin or paternal origin. If it is maternally derived the fetus is diagnosed with AS (a paternally derived genetic disruption is indicative of Prader-Willi Syndrome).<ref name="PMID17020468"><pubmed>17020468</pubmed></ref>		DNA methylation analysis using [[#Glossary \| '''Amniocytes''']] is usually the first test carried out in molecular diagnosis of AS.<ref name="PMID18059071"><pubmed>18059071</pubmed></ref> An abnormal result is followed up by either a FISH or array CGH analysis to search for a deletion on chromosome 15. If they produce a normal result, then UPD testing using DNA polymorphysims is carried out. If there is no evidence of UPD, other DNA analysis tests are used search for an imprinting centre deletion.<ref name="PMID9792887"><pubmed>9792887</pubmed></ref> A normal DNA methylation analysis is followed by a UBE3A sequence analysis.<ref name="PMID18059071"/> In addition, a parent of origin test is also done to determine if the genetic disruption is of maternal origin or paternal origin. If it is maternally derived the fetus is diagnosed with AS (a paternally derived genetic disruption is indicative of Prader-Willi Syndrome).<ref name="PMID17020468"><pubmed>17020468</pubmed></ref>