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PATH30001 - Mechanisms of Disease > Lecture 26 - Genetic Disorders > Flashcards

Lecture 26 - Genetic Disorders Flashcards

1
Q

In general, what are the categories of genetic disorders?

A
  • Chromosomal abnormalities
  • Single gene disorders
  • Polygenic / multifactorial disorders
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2
Q

What is the name for abnormal chromosome number disorders?

A

Aneuploidies

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3
Q

What is the mechanism of aneuploidies?

A

Missassortment (non-disjunction) in meiosis

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4
Q

What are the sub-categories of aneuploidies?

A

Trisomy: extra single chromosome

Monosomy: deletion of a single chromosome

Polyploidy: multiples of haploid number of chromosomes

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5
Q

What is an example of polyploidy?

A

Triploidy: human is 3n instead of 2n

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6
Q

What is the mechanism of structural abnormalities?

A
  • Rearrangement or deletion
  • During crossing over

examples:
• Translocations
• Inversions
• Duplications

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7
Q

Why would genetic testing be carried out?

A

Presence of certain clinical indications:

  • Problems with early growth and development
  • Stillbirth and neonatal death
  • Fertility problems
  • Family history
  • Neoplasia
  • Pregnancy in older women
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8
Q

Describe Down syndrome

A

• Collection of facial and physical features

Associated with:
 • Intellectual disability
 • Congenital heart disease
 • Congenital GIT abnormalities
 • Leukaemia
 • Immunological defects
 • Premature ageing
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9
Q

Describe the premature ageing seen in Down syndrome

A

Alzheimer-like dementia

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10
Q

What is the classical cytogenic analysis of Down syndrome?

A

Karyotyping:
• Presence of three chromosome 21’s

Process:

  1. Lymphocytes isolated
  2. Grown in culture, diving
  3. Arrested in metaphase (chromosomes are the most dense)
  4. Staining
  5. Observation
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11
Q

Is trisomy 21 seen in all cases of Down syndrome?

A

No, only in 95% of cases

95%: Trisomy 21

5%: Unbalanced translocations

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12
Q

What is FISH?

What is it used for?

A

Fluorescence in situ hybridisation

Used for detection of trisomy 21:

  1. Cells taken from foetus
  2. Fluorescently marked probe for a given chromosome
  3. Interphase (non-dividing) cells given the probe
  4. Observation of 3 coloured dots → three of the given chromosome
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13
Q

How many chromosomes do humans have?

A

46:
22 autosomes
2 sex chromosomes

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14
Q

Describe the process of balanced translocation

Compare with unbalanced translocation

A
  1. Balanced
    • No net gain or loss of genetic material

• Reciprocal translation between two non-homologous chromosomes
e.g. 21 and 3:
• Breakage in both chromosomes
• The fragment rejoins on the other chromosome

  1. Unbalanced
    • Net gain or loss of genetic material
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15
Q

Describe Robertsonian translocation

Does it result in a disease phenotype?

A

Translocation between two acrocentric chromosomes

Short arms are lost
Only one centromere

Phenotype?
• Depends on whether the translocation is balanced or unbalanced

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16
Q

What are acrocentric chromosomes?

A

Chromosome in which the centromere is very close to the end of the chromosome

There are only 5 acrocentric chromosome in humans
 • 13
 • 14
 • 15
 • 21
 • 22
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17
Q

In which phase of the cell cycle is FISH performed?

A

Interphase

The cells are non-dividing

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18
Q

What proportion of DS cases are inherited unbalanced translocations?

A

1-2%

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19
Q

What are inherited DS cases due to?

Describe this

A

Unbalanced translocation

One of the parents is a carrier of unbalanced translocation
i.e. one of the gametes has two versions of a given chromosome (21)

e.g. 
Parent 1° gamete: (14;21) & 21
Parent 2° gamete:  14 & 21
-- fertilisation --
Zygote: (14;21), 21, 14, 21

The zygote has three copies of Chromosome 21

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20
Q

What are ‘DNA chips’?

Describe their use

A

Microarrays

Can look at:
• SNPs
• Chromosome n°
• CNVs

Process:
• Glass slide
• Imprinting short DNA sequences onto slide (oligonucleotides)
• Patient’s DNA sample hybridised onto oligonucleotides on the slide

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21
Q

What are SNPs?

A

Single nucleotide polymorphisms

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22
Q

What are CNVs?

A

Copy number variations

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23
Q

What are CMAs?

Describe their use

A

Chromosome microarrays

Allows discovery of micro deletions that are too small to be seen in FISH or karyotyping

Wolf-Hirschhorn syndrome:
• Microdeletion at the terminal region of Ch 4
• The read out shows dip at the very end
• Hybridisation of the patient’s DNA and ‘reference’ DNA (this is a controversial idea)
• If there is an imbalance of the hybridisation, we know that there is a microdeletion
• This is too small to be seen in FISH or karyotyping

24
Q

What are some of the ways chromosome abnormalities are analysed?

A
  • FISH
  • Karyotyping
  • Microarrays
  • CMAs
25
Q

Give examples of single gene disorders that are:
• Autosomal dominant
• Autosomal recessive
• X-linked recessive

A

Autosomal dominant:
• Huntington
• Osteogenesis imperfecta

Autosomal recessive:
 • CF
 • Thalassaemias
 • Sickle cell disease
 • Hereditary haemochromatosis

X-linked recessive:
• Duchenne muscular dystrophy
• Haemophilia

26
Q

From whom are the mitochondria inherited from?

A

The mother

27
Q

What is:
• Penetrance
• Variable expressivity
• Genetic heterogeneity?

A

A disorder may be ‘single gene’
However, there is variable severity of the phenotype

Environmental factors etc.

28
Q

How are single gene disorders tested for?

A

Pathology settings:
• PCR + RFLP analysis

Increasingly used:
• Microarrays
• Panels of gene mutations
• DNA sequencing

29
Q

Which gene is mutated in β-thalassaemia?

Describe this gene

A

β-globin chain genes

Mutation in transcription start site:
T → C
→ Decreased transcription of β-globin chain gene

→ Decreased (or lack of) β-globin chain production in those affected

30
Q

Describe the structure of adult Haemoglobin

Compare this with β-thalassaemia

A

Adult form of Haemoglobin:
“heterotetramer’
• Two β-globin chains
• Two α-globin chains

In β-thalassaemia:
‘homotetramer’
• Four α-globin chains

31
Q

What is bad about the Hb in β-thalassaemia?

A

α4 homotetramers lead to the destruction of RBCs

→ anaemia

32
Q

What is the main clinical feature of β-thalassaemia?

A

Anaemia

33
Q

Describe how β-thalassaemia is tested for

A

PCR + RFLP analysis

  1. PCR of β-globin chain gene
  2. Cut with NcoI (restriction enzyme)
    3a. No mutation:
    • Cutting

3b. Mutation:
• No cutting

  1. Gel electrophoresis:
    a. No disease: 250 bp & 900 bp fragments
    b. Disease: 1200 bp fragments
34
Q

Describe polygenic disorders

A

Additive contribution of several genes to the disease phenotype

Input of each of the genes not necessarily equal

Variables are continuous

35
Q

Give examples of continuously variable phenotypes

A 
Height
Body weight
Cholesterol levels
Diabetes
Asthma
Heart disease
36
Q

Compare hereditary component of monogenic and polygenic disorders

A

Monogenic: high hereditary component

Polygenic: low hereditary component

37
Q

How are genes responsible for polygenic disorders identified initially?

A

GWAS

SNPs that are shared with much greater frequency among individuals with the same phenotype than among others

38
Q

How are complex genetic diseases tested for?

A

Same as single-gene conditions

39
Q

Why is genetic testing performed?

A
  • Clinical diagnosis
  • Carrier testing
  • Pre-symptomatic / predictive testing
40
Q

Why is prenatal diagnosis performed?

A
  • Help making informed choices
  • Reassurance with normal results
  • Risk information
  • Choice of termination
  • Psychological preparation
  • Planning of delivery and care
41
Q 
Describe the following tests:
 • CVS
 • Amniocentesis
 • PGD
 • NIPT
A
  1. CVS: chorionic villus sampling
    • Invasive; risk of miscarriage
    • Placental tissue
  2. Amniocentesis
    • Amniotic fluid containing sloughed off foetal cells
    • Invasive, risk of miscarriage
    • Ultrasound
  3. PGD: pre-implantation genetic diagnosis
    • 1 or 2 cells taken from dividing zygote
    • Only can be done in IVF
    • Unaffected embryos implanted
4. NIPT: non-invasive pre-natal testing
 • Foetal cells and DNA/RNA in maternal blood
 • Introduced in 2013
 • Based on next generation sequencing
 • Marketed as genetic screening
42
Q

Compare how TOP is performed in CVS and Amnio

A

CVS:
• Aspiration under general anaesthetic

Amnio:
• Prostaglandin induction of labour

43
Q

Compare risk of miscarriage in CVS and amnio

A

CVS: about 1%

Amnio: about 0.5%

44
Q

What is the incidence of Down syndrome?

A

1 in 660

45
Q

What are the pros/cons of FISH and Karyotyping

A

FISH:
• Much faster than Karyotyping
• Not as definitive as karyotyping

Karyotyping:
• Slower, because cells must be cultured and grown up

46
Q

What is genetic screening used for?

Which people are screened?

Are they effective?

A

Identification of individuals at high risk of having or transmitting a specific genetic disorder

Who?
• General population
• Groups at risk

Efficacy:
• Not always definitive
• False positive and negatives occur
• Not all genes and mutations can be picked up

47
Q

When would PCR+RFLP analysis be performed?

A

When the mutation is known, and the mutation is suspected in a family

This is because this is a very specific test

e.g. B-thalassaemia

48
Q

Compound heterozygosity?

A

Two different mutations leading to disease

49
Q

Why is genetic screening carried out?

A
  • Prevention of disease
  • For early treatment
  • Future reproductive options
  • Decrease social and financial burdens
50
Q

What are the criteria of screening for a genetic condition?

A

As defined by WHO:

Must be:
• Important, severe, common health problem
• Preventable or treatable
• Screening is simple, safe, reliable, acceptable and relatively inexpensive
• Education and counselling available

51
Q

What type of population genetic screening is carried out in Victoria?

A
  • Pre-natal
  • Newborn
  • Pre-conception carrier screening
52
Q

Describe how pre-natal screening can be carried out

A
  1. Ultrasound
  2. Maternal serum screening
  3. NIPT screening
53
Q

Which diseases does newborn screening look for?

A
  • CF
  • Phenylketonuria (PKU)
  • Congenital hypothyroidism
  • Some rare metabolic conditions
54
Q

When is pre-conception carrier screening carried out?

A
  1. Groups with higher carrier frequencies in ethnic groups

e.g.
• Ashkenazi Jewish high school students for Tay Sachs

  1. ad hoc
    • CF
    • Haemoglobinopathies
55
Q

What is personalised medicine?

How is it carried out?

A

Individualised care based on genotype

How:
• Whole genome sequencing
• others… (new technologies)

PATH30001 - Mechanisms of Disease (34 decks)

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