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1	Genetic Mechanisms in Angelman Syndrome Jill Clayton-Smith St.Mary’s Hospital Manchester
2	Angelman Syndrome Severe learning disability Ataxic, jerky movements Seizure disorder Absent speech Characteristic facial features Happy, sociable affect
3	1. Angelman Syndrome is due to a deletion of 15q11-13 in 65% of cases
4	Deletions are detected more easily by FISH analysis
5	Principle of FISH
6	Principle of FISH
7	15q11-13 deletions tend to be of a similar size
8	Chromosome 15q11-13 is an imprinted region
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10	Maternal and Paternal 15q11-13 show Differential Methylation
11	Some deletions arise due to a parental chromosome rearrangement
12	Parental chromosome rearrangement
13	2. Angelman Syndrome May Arise as a Result of Paternal Uniparental Disomy
14	3. Angelman Syndrome may arise due to failure to reset the parental imprint during gametogenesis
15	The Imprinting Centre Controls Setting of the Parental Imprint
16	Imprinting Defects Mutation within the imprinting centre No mutation identified. Failure of imprint to be reset is a chance (stochastic) event Mosaic imprinting defect
17	4. Angelman Syndrome may arise due to a mutation within the UBE3A gene
18	UBE3A mutation
19	UBE3A gene Responsible for producing a protein called a ubiquitin protein ligase which is involved in protein degradation within the brain Only the maternal copy is active in brain The gene works in specific regions of the brain involved in learning, memory and movement
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22	UBE3A mutation may be familial
23	UBE3A mutations may be familial due to the mother carrying the fault in her ovaries, but not blood
24	UBE3A mutations Found in 80% familial AS and 20% sporadic AS Not present in mother in 75% sporadic cases Mother carries mutation in 20% cases Significant number of mothers are gonadal mosaics so pre-natal diagnosis recommended
25	5. Clinical features of AS with no genetic abnormality Not AS. Consider other diagnoses. Mutations not detectable by current techniques Another genetic mechanism Another transcript of UBE3A Another gene Mosaicism
26	Summary
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28	Algorithm for Genetic Testing
29	Lessons We Have Learned Not everyone with AS has the typical features The behaviour is the most consistent feature. If it’s typical, keep looking at the AS gene/region There is a lot of overlap in ability between del/UPD/UBE3A/Imprintor Mosaics are likely to be more difficult to pick up UBE3A mutations are not that uncommon; >50 detected in our lab so far
30	Questions?