5: Phenotypic variability

Question 1

Phenotypic variability is

Answer 1

the variation of gene expression in the same disease in different individuals
- may not have same symptoms or presentations

Question 2

5 causes of phenotypic variability

Answer 2

Environment e.g low iron intake
Sex - expression of a gene varies by sex e.g hereditary haemochromatosis
Modifiers - expression of gene directly affected by presence of other genes e.g CF
Mutation - different mutated subtypes of same disease have different presentations e.g Duchenne vs Becker dystrophy
Unstable - trinucleotide repeat disorders - incr. number of nucleotide repeats (>27) cause more severe phenotypes throughout generations e.g Huntingtons more severe in future generations

Question 3

Genetic testing is carried out as a part of

Answer 3

pre-natal screening

Question 4

When are genetic tests carried out in pregnancy

Answer 4

11-14 week : dating pregnancy, diagnose multiple pregnancy, major foetal abormalities, early miscarriage. assess risk of downs syndrome (nuchal translucency)
20-22 week : look for 11 rare conditions, more detailed- bones, heart, brain, spinal cord, face, kidneys

Question 5

If any anomalies are found in pre-natal screening what two paths can be taken

Answer 5

Non- invasive test
Invasive tests

Question 6

Non-invasive tests include

Answer 6

Maternal blood test
Cell free foetal DNA (cffDNA)

Question 7

Invasive tests include

Answer 7

Chronic villus sampling (CVS) (11-14 weeks)
Amniocentesis (16+ weeks)

Question 8

Nuchal Translucency tests

Answer 8

don’t indicate chromosomal abnormality, just identify higher risk of one
- screening test not diagnostic test

Question 9

In a nuchal translucency test

Answer 9

Fluid from the back of the fetal neck collected between 10-14 weeks

Question 10

Increase nuchal translucency test result can indicate

Answer 10

> 3mm
chromosome abnormalities
NT + maternal age detects up to 75% of down syndrome with 5% false postive rate

Question 11

Birth defects associated with incr. nuchal translucency results

Answer 11

cardiac anomalies
pulmonary defects (diaphragmatic hernia)
renal defects
abdominal wall defects
- skeletal dysplasia

Question 12

prenatal testing is arranged following

Answer 12

abnormal findings at nuchal/mid-trimester scan and in women with high risk of down syndrome or previous history of genetic disease

Question 13

4 aims of prenatal testing

Answer 13

to inform and prepare parents for birth of an affected baby
to allow possible in utero treatment
to aid managing the remainder of the pregnancy
to allow termination of affected fetus

Question 14

Maternal serum screening is an example of

Answer 14

Non-invasive genetic testing
not fully accurate

Question 15

Maternal serum screening tests for

Answer 15

maternal serum markers in the blood to detect increased risk of fetal trisomy 21/18 and neural tube defects

Question 16

Combined MSS test

Answer 16

1st trimester (11-14 weeks) tests for hCG, PAPP A

Question 17

Second MSS test

Answer 17

2nd trimester (16-20 weeks) tests for hCG, AFP, UE3

Question 18

Cell-Free foetal DNA test is an example of a

Answer 18

Non-invasive genetic test
usually carried out privately

Question 19

A cell-free foetal DNA test analyses

Answer 19

placental DNA in maternal plasma
first detectable at 4-5 weeks but most accurate at 9 weeks

Question 20

Chorionic Villus Sampling is an example of

Answer 20

an invasive genetic test

Question 21

Chorionic Villus Sampling consists of

Answer 21

Transabdominal/vaginal sample taken of chorionic villi as it contains some foetal DNA

Allows for earlier results than amnio for abortion, but 1-2% risk of miscarriage so only done if risk is known

Question 22

Amniocentesis is an example of an

Answer 22

invasive genetic test

Question 23

Amniocentesis consists of

Answer 23

sample of cells taken from amniotic fluid containing foetal cells
Risk of Rh sensitization and infection
1% risk of miscarriage

Question 24

What invasive test is carried out first

Answer 24

Chorionic Villus sampling

Question 25

Further genetic testing following non-invasive and invasive tests

Answer 25

CGH Array
Trio Exome

Question 26

CGH Array consists of

Answer 26

recommended once concerns on 20 weeks scan
looks for chromosomal imbalances to pick up diseases, may require testing of parents to interpret

Question 27

Trio Exome test consists of

Answer 27

Full genetic sequencing, offered where previous pregnancies have significant abnormalities

Question 28

4 Reproductive Options

Answer 28

Natural conception
Egg/ Sperm donors
Adoption
Pre-implantation genetic diagnosis

Question 29

Egg/Sperm donation in the UK

Answer 29

UK HFEA licensed fertility centre - conform to strict medical, ethical, legal standards

Question 30

Adoption in the UK

Answer 30

Registration and Checks. Social service involvement - assessment and aproval

Question 31

Pre-Implantation Genetic Diagnosis

Answer 31

Uses IVF with genetic testing before implantation
1. Stimulation of ovaries
2. egg collection
3. insemination and fertilisation
4. embryo biopsy
5. embryo testing
6. embryo transfer
7. pregnancy test

Question 32

PGD referal criteria

Answer 32

Known risk of having a child affected by serious genetic condition
Female partner has hormone levels suggesting response to treatment

HFEA have to issue a license for each genetic condition / indication
Eligible couples usually funded for 3 rounds of PGD