Epigenetic

Question 1

What is an epigenetic trait

Answer 1

An epigenetic trait is a stably heritable phenotype resulting from
changes in DNA without alterations to the DNA sequence

Question 2

Examples of epigenetics

Answer 2

o DNA methylation
o non-coding RNAs (e.g. microRNA, lncRNA)
o Histone methylation and other modifications
o RNA methylation

Question 3

Where does Methylation of DNA in mammalian cells occur
- CpG methylation of gene promoters causes…
-CpG methylation is transmitted through?

Answer 3

cytosine residues in CpG
islands

CpG methylation of gene promoters causes transcriptional silencing

CpG methylation is transmitted through cell divisions by methyltransferase
enzyme activity
Methylation can be reversed if methyltransferases are inhibited or sequestered (as occurs in early
development)

Question 4

What is X inactivation

Answer 4

A combination of DNA methylation and a non-coding RNA called XIST working
together - random inactivation of either maternal or paternal chromosome/allele.

Question 5

What is genomic imprinting

Answer 5

• Restriction of expression to either the maternal or paternal allele in somatic
  diploid cells
• Causes different expression from genetically identical alleles based on parent of
  origin

Question 6

What are the Two different syndromes caused by
abnormalities in the maternal or paternal alleles at close imprinted loci

Answer 6

Prader willi syndrome and angelman syndrome

Question 7

What is pradar willi syndrome symptoms
- mutation type

Answer 7

• Failure to thrive in infancy and early childhood
• Neonatal hypotonia
• Rapid weight gain after 1 year
• Behavioural obesity and short stature
• Almond-shaped eyes
• Hypogonadism
• Small hands and feet
• Skin hypopigmentation
• Behavioural problems

The paternal allele of a region of chromosome 15 (15q11-q13) is deleted
or not present due to uniparental disomy
* The maternal allele cannot take over since it silenced due to imprinting. In particular, causing absence of the SNRPN and NDN genes along with
clusters of snoRNA genes

Question 8

Symptoms of angelman syndrome

Answer 8

• Typically a happy, open-mouthed expression
• Tongue thrusting
• Mental retardation
• Motor retardation, jerky movements
• Ataxia
• Hypotonia
• Seizures
• Sleep disturbances
• Happy children, laugh frequently
• Skin hypopigmentation

Question 9

Causes of angelman syndrome

Answer 9

• The maternal allele of a region of chromosome 15 (15q11-q13) is deleted
  or inactivated
• The paternal allele cannot take over since it silenced due to imprinting
• In particular causing absence of UBE3A gene expression

Question 10

PW vs angelman chromosome affected

Answer 10

Pradar= paternal copy deleted

Angelman
= maternal copy deleted

Question 11

Importance of Methylation in Cancer

Answer 11

Therapeutic Target
* Abberant Methylation is a hallmark of cancer - switching off global
methylation (e.g. 5-azacytidine) via blocking methyltransferases can
reactivate gene expression

Biomarker Target
* Methylation signatures are cell type and disease state specific
* Testing of DNA in tissues or biofluids can indicate diagnosis, prognosis

Question 12

What is a Dynamic Mutation
-common diseases caused

Answer 12

• Progressive expansion of repeat sequences; mainly triplet repeats

Huntington disease
Myotonic dystrophy
Cerebellar ataxias
Fragile X disease A

Question 13

Clinical Diagnosis of HD
-gp level

Answer 13

• Progressive motor disability involving both voluntary and involuntary
  movement
• Mental disturbances including cognitive decline and/or changes in
  personality
• Family history consistent with autosomal dominant inheritance

Question 14

Allele sizes of huntingtons

Answer 14

Normal: ≤ 26 CAG repeats
- no clinical effects, stable in transmission

Intermediate: 27 - 35 CAG repeats
- no symptoms of HD, but possibility of child inheriting “mutant allele” if affected parent is
male

Mutant: ≥ 36 CAG repeats
- reduced penetrance alleles: 36 - 39 repeats
- full penetrance alleles: ≥ 40 repeats

Question 15

HD risks to family members

Answer 15

Parents of proband
* most individuals with HD have an affected parent (de novo mutations causing HD
are rare)
* either asymptomatic parent of an affected individual may have a reduced
penetrance allele (CAG repeat 36-39)

Sibs of proband
* risk depends on genetic status of parent

Offspring of proband
* each child of individual with HD has a 50% chance of inheriting the mutation as a
result of heterozygosity for the HD mutant allele (homozygosity is very rare)

Question 16

Molecular Genetic testing of HD

Answer 16

Diagnostic (confirmatory)
* confirms disorder
* undertaken after assessment by neurologist

Predictive (presymptomatic)
* confirms mutation that confers high risk of disorder prior to onset of disease
* only undertaken after neurological assessment and counselling

Prenatal
* issues regarding disclosure of status of parent
* exclusion testing (avoids definitively testing a parent by looking for the inheritance of
affected grandparental allele to give a ’50% risk’)