Lecture 9: Genetic Screening

Question 1

what are the specific issues with genetic screening based on?

Answer 1

• Permanent results

- Implications for family members

Question 2

Explain what ACCEE is

Answer 2

• Analytical validity – how well does the test measure what it aims to measure?
• Does it measure what we want to measure
• Clinical validity – how well does the test predict future health?
• Pharmacogenetics-> used to predict response to drugs
• Clinical utility – does the test alter health outcomes?
• Is health outcomes affected?
• Ethical validity – is the test ethical?
• Collection of sample could be ethically invalid
• Outcome of test leaves patient limited to option- e.g, can’t do abortion because forbidden by their culture = leaves only to carry on pregnancy
• Taking multiple sample from someone who doesn’t understand what is happening-> ethical?
• Economics – is it financially viable?
• Cost of obtaining + analysing sample
• E.g, cff DNA less invasive-> less use of specialist equipment for invasive testing= viable

Question 3

Define true positive

Answer 3

Test positive+ has condition

Question 4

Define false positive

Answer 4

Test positive+ doesn’t have condition

Question 5

Define false negative

Answer 5

Test negative+ has condition

Question 6

Define true negative

Answer 6

Test negative+ doesn’t have condition

Question 7

Define and give equation for sensitivity

Answer 7

• Sensitivity: ability to detect the condition out of all the people who have the condition

Question 8

Define and give equation for specificity

Answer 8

• Specificity: detects someone without the condition out of all the people who do not have the condition

Question 9

Define and give equation for false positive

Answer 9

• False positive: test result is positive yet the person does not have the condition. Given as a proportion of the whole population

Question 10

Define and give equation for false negative

Answer 10

• False negative: test result is negative yet the person does have the condition. Given as a proportion of the whole population

Question 11

Explain how who should be screened is determined

Answer 11

• Whole population-> not economically viable for all diseases
• Targeted populations
• Age
• Definition of ‘old age’
• can be not definitive-> out + close to boundaries of age range + still be or offspring affected= DS
• Race
• particular disease can be viewed as ‘bad trait’ associated with race
• E.g, sickle cell anaemia prominent with Afro-Caribbean race
• Can become ostracised + affect employability once declared publicly
• Family history
• E.g, Ashkenazi Jews prone to breast cancer
• Amish pop. is small community-> interbreeding

Question 12

Explain what NICE is and their role

Answer 12

• Provide national guidance and advice to improve health and social care
• Make recommendations on the use of new medicines and medical technologies
• Define healthcare pathways

Question 13

List the factors to consider when implementing a new test

Answer 13

- ACCEE
\+ - disease incidence
- disease pathology 
- turnaround time 
- sample + analysis

Question 14

Describe what the foetal anomaly screening programme detects

Answer 14

• Neural tube defects: anencephaly, spina bifida
• Organ development: heart abnormalities, renal agenesis
• Agenesis:failure of an organ to develop during embryonic growth and development
• Skeletal dysplasia – achrondroplasia
• Skeletal dysplasia: abnormalities of cartilage and bone growth, resulting in abnormal shape and size of the skeleton
• Achrondroplasia: bone growth disorder that causes disproportionate dwarfism
• Cleft lip/palate, diaphragamatic hernia, abdominal wall
• Cleft lip/palate: gap or split in the upper lip and/or roof of the mouth
• Diaphragamatic hernia: hole in the diaphragm-> Organs in the abdomen move through hole + upwards into a baby’s chest
• Trisomy 18, Trisomy 13, Trisomy 21
• T18= Edward’s syndrome
• T13= Patau’s syndrome
• T21= DS

Question 15

Explain how foetal anomalies are screened

Answer 15

• Biochemical analysis of maternal serum
• Ultrasound scans, 10-14- and 18-21-weeks gestation
   10-14= done for mum to identify gestational diabetes + HIV that can be passed onto offspring + dating scan (how far long)
   18-21= done for detecting foetal anomalies

Question 16

Explain and compare the advantages of ultrasound

Answer 16

Advantages:

• non-invasive
• no known risk to mother or feotus
• relatively cheap to perform

Disadvantages:

• expensive equipment
• skilled & experienced personnel
• fetal position-> Position makes it unable to see anomalies
• maternal BMI-> more of ultrasound absorbed by subcutaneous fat rather than pass through and reflected for image to be formed

Question 17

Describe what the newborn blood spot is and what it is used for

Answer 17

• Heel pricked of new born-> collect blood sample on Guthrie card
• Used to detect inherited metabolic diseases

Question 18

List the inherited metabolic diseases it can identify

Answer 18

Phenylketonuria (PKU)
•Medium chain acyl-CoA
dehydrogenase deficiency
(MCADD)
•Maple syrup urine disease
(MSUD)
•Isovaleric acidaemia (IVA)
•Glutaric aciduria type 1
(GA1)
•Homocystinuria (HCU) 
• Sickle cell disease
• Cystic fibrosis
• Congenital hypothyroidism

Question 19

Explain the pathophysiology for PKU

Answer 19

• Gene for phenylalanine hydroxylase mutated= abnormal protein -> doesn’t convert phenylalanine to tyrosine
• Increase + build-up of phe and decrease of tyr
• Build-up -> causes phe to convert to phenylketones
• Decrease in tyr-> causes depletion of neurotransmitters + melanin

Question 20

State when neonatal screening for PKU is done and why at this time

Answer 20

5 days old-> allow metabolite to accumulate

Question 21

Describe the clinical features of PKU

Answer 21

• Blond hair, blue eyes-> due to lack of melanin
• Intellectual impairment-> due to lack of neurotransmitters
• Seizures-> due to lack of neurotransmitters

Question 22

Explain how PKU can be treated

Answer 22

• Very effective + easy: Severely restrict dietary intake of phenylalanine (low protein diet)
• Phenylalanine - an essential amino acid= can’t be produced by body-> has be sourced externally by diet
• PKU present for 1st 20yrs of life
• After approx.20yr-> relax diet in adulthood + except pregnancy

Question 23

Name the disease that is identified using adult screening

Answer 23

Familial hypercholesterolemia (FH)

Question 24

State the mode of inheritance for FH

Answer 24

• Autosomal dominant

Question 25

State how FH is characterised

Answer 25

• Characterised by high LDL-cholesterol: 200-400 mg/dL (N: 75-175 mg/dL)

Question 26

State what FH can lead to

Answer 26

• Causes and leads to premature coronary artery disease, myocardial infarctions & death

Question 27

State what can see around the tendons of people with FH

Answer 27

• Tendon xanthoma= deposits of LDL cholesterol

Question 28

Explain the pathophysiology & treatment for FH

Answer 28

• Sources of LDL cholesterol: Diet (external) + Synthesis(internal)
• LDL-cholesterol taken up by LDL-Receptor
• Feedback mechanism maintains LDL levels in blood
• LDL-R is defective in FH patients
• Treatment: statins inhibit cholesterol synthesis

Question 29

Evaluate FH pop. screening

Answer 29

• Good idea:
• Common condition
• Serious health implications
• Effective treatment
• Increase in life expectancy-> more conscious of diet
• However:
• LDL-cholesterol levels not sufficiently specific or informative in younger patients
• > can have high LDL and not have FH
• Genetic testing is expensive and complicated-> 18 exons

Question 30

Explain what casade screening is

Answer 30

• Test affected + test relatives
• If relative pos. -> test family of that relative
• Keep continuing to identify individuals who are affected + do not know

Question 31

Evaluate cascade screening

Answer 31

Advantages:

• Application of diagnostic test to those individuals at most risk of having the disease.
• Cost-effective

Disadvantages:

• Time consuming-> have to get in contact with family + relatives + obtain from each a sample
• Delay in diagnosis, delays treatment

Question 32

Explain how trivialities of cascade screening

Answer 32

• Have to consider how to deliver news to relatives that they could have disease-> inform by using leaflets + advise for testing