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Learning disability > PWS/AS > Flashcards

PWS/AS Flashcards

1
Q

What is imprinting?

A

Differential expression of genes by parent of origin

May be cluster of genes controlled by IC (cis acting)

Most commonly methylation of cytosine at CpG nucleotides

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2
Q

What is the imprinted region associated with these disorders?

A

15q11-q13

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3
Q

Paternal 15q11-q13

A

-critical region unmethylated

- several genes preferentially expressed:
MAGEL2
MKRN3
NDN
PWRN1
SNURF-SNRPN
snoRNA genes
  • Deficiency or SNORD116 results in key characteristics of PWS
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4
Q

Maternal 15q11-q13

A
  • CpG islands associated with paternally expressed genes are methylated
  • methylation prevents TF binding and assembly of transcriptional machinery
  • UBE3A expressed (brain)
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5
Q

Genetic mechanism of PWS

A

Loss of paternally expressed genes within 15q11-q13

De novo deletion 75-80%
Maternal UPD 20-25%
Imprinting defect (excluding del) 1%
IC deletion 10-15%
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6
Q

Genetic mechanisms in AS

A

Loss of maternally expressed genes

  • de novo deletion 70-75%
  • paternal UPD 3-7%
  • Imprinting defect (excluding del) 2-3%
  • IC del 10-15%
  • UBE3A mutation 10% (normal methylation pattern)
  • Unknown 10%
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7
Q

PWS clinical phenotype

A 
Hypotonia
Failure to thrive neonatal
Mild LD
Hyperphagia and obesity later in dev
Male hypogonadism
Short stature
Small hands and feet
Behavioural problems
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8
Q

AS clinical phenotype

A
  • Severe mental retardation
  • Lack of speech
  • Hyperactivity
  • Inappropriate laughter
  • Gait ataxia
  • Seizures
  • Microcephly
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9
Q

Mechanism of deletion (common break points)

A

Non-allergic homologous recombination between low copy repeat regions

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10
Q

UPD

A

Both Chr originate from same parent

Heterodisomy (MI) or isodisomy (MII)

Most commonly maternal due to non-dysjunction (maternal age effect)

Can result from early mitotic error, may result in somatic mosaicism

Isodisomy may result from gamete complementation

Low recurrence risk unless carry Robertsonian translocation

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11
Q

Other imprinting disorders

A
  • Beckwith-Weidemann syndrome (11p15)
  • Silver-Russell syndrome (11p15)
  • UPD14 (14q32)
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12
Q

Describe bisulphite PCR

A
  • Methylation pattern at the SNRPN locus within the PWS/AS critical region
  • Treat DNA with sodium bisulphite
  • Converts unmethylated C residues to uracil (deamination)
  • PCR primers specific for methylated/unmethylated
  • Common primer in unmethylated region acts as conversion control
  • detects 99% cases of PWS and 80% AS
  • cannot establish disease mechanism
maternal = methylated
paternal = unmethylated
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13
Q

Heterodisomy

A

Pair of non-identical chromosomes inherited from one parent (meiosis I error)

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14
Q

Isodisomy

A

Single chromosome from one parent duplicated (meiosis II error)

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15
Q

Trisomy rescue

A

Conception trisomic, 1 homologue is lost by anaphase lag in early cell division

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16
Q

Robertsonian translocation

A

Carriers of Robertsonian translocations involving chromosome 15 at increased risk of having an affected child

Can lead to UPD via monosomy or trisomy rescue

17
Q

Imprinting defects

A
  • Failure to set the correct parental expression pattern
  • Often de novo
  • 10-15% IC microdeletion
  • Maternal IC deletion inherited from mother = AS
  • Paternal IC deletion inhertied from father = PWS
  • Deletion up to 50% recurrence risk
18
Q

Describe the PWS/AS IC

A

It contains two critical regions:

AS-SRO (shortest region of deletion overlap)
PWS-SRO

19
Q

In what situation is an IC mutation mosaic in AS?

A

A third of AS patients with a primary epimutation show somatic mosaicism (occurred after fertilisation).

20
Q

PWS pathogenesis

A

No individual protein coding gene linked to phenotype

Knockout mice for each gene may show some features of PWS

Loss of expression of SNORD116 snoRNA cluster thought to cause phenotype

A microdeletion in this cluster has been identified in a child with PWS

May regulate alternative splicing

21
Q

AS pathogenesis

A

Caused by loss of UBE3A expression in the brain

UBE3A encodes a E3 ubiqutin ligase protein that targets certain proteins for degradation

Aberrant protein degradation interferes with correct neuronal development

22
Q

Disadvantages of bisulphite PCR

A
  • false positive due to snp under primer
  • false positives due to incomplete DNA modification removed by control common primer that binds converted DNA
  • no information about disease mechanism
  • cannot detect mosaicism (false neg)
23
Q

MS-MLPA

A

Allows for detection of methylation pattern and copy number changes

Can detect larger deletions and IC deletion

Requires 5 control samples

Methylation sensitive restriction enzyme added to half of the ligation products (Hha1)

Unmethylated DNA is digested and not amplified

Methylation ratio established by comparing probes in digested/undigested reactions

24
Q

MS-MLPA disadvantages

A

-sensitive to PCR contaminants
-sensitive to DNA quality
-Cannot detect UBE3A mutations
Can generate false positives due to snp under probe site (confirm single probe del)
-Expensive
-Cannot differentiate between UPD and imprinting defect (no IC del)

25
Q

Referral types

A

PWS diagnostic:

  • babies hypotonia
  • children with obesity/hyperphagia/behavioural problems

AS diagnostic:
-phenotypic features

Prenatal:

  • parents who carry chr 15 translocation
  • IC deletion identified in previous child
  • UBE3A mutation in family
26
Q

PWS differential diagnosis (hypotonia in infants)

A

Congenital myopathies
Congenital myotonic dystrophy
Type I spinal muscular atrophy

27
Q

AS differential diagnosis

A 
Rett syndrome (girls)
Mowat-Wilson syndrome (ZFHXIB)
Pitt-Hopkins syndrome (TCF4)
Deletions at:
1p36
17q21
22q13
28
Q

PWS differential diagnosis (LD, obesity)

A

Cohen syndrome
Borjesson-Forssman-Lehman syndomre
Bardet-Biedl syndrome

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