integrated approach to genetic disorder Flashcards
What is CF
Gene makes protein chloride transport channel (CFTR) which takes Cl out of the cell and with this, water and Na follow. Allowing cillia to move the mucus freely
HOWEVER
if there is an abnormal gene, there is an abnormal protein leading to no/little Cl transport out of the cell. Water and Na follow and so remain in the cells, leading to thickened mucus blocking airways (thick secretions)
The newborn screen for CF
- Blood trypsin (pancreatic enzyme)
- Thick secretions block the
pancreatic duct – enzymes cannot move into GI tract
Enzymes are then absorbed
into the bloodstream - If high → 3 common CF genes
Issue with the screen test
For 5 positive screen approx. 1 has true CF
Positive on the newborn screen
Next steps?
- Sweat test
- Genetics from baby
- Stool sample for enzymes
3 types of diagnosis from CF testing
CF carrier:
* Negative sweat test
Chl <30mmol/L
* 1 gene only
Cystic fibrosis:
* Positive sweat test
Chl > 60 mmol/L
* 1 or usually 2 genes
Cystic Fibrosis Screen Positive Indeterminant Diagnosis:
* Intermediate sweat test
Chl 30-60 mmol/L
* 1 gene OR 2 genes with one being of unknown significance
Features of CF
- Recurrent pneumonias
→ progressive lung disease - Failure to thrive/poor growth
- Nasal polyps
- Sinusitis
- Diabetes
- Liver disease
- Gallstones
- Portal hypertension
- Distal intestinal obstructive syndrome,
constipation - Vitamin deficiencies
- Bone disease
- Fertility concerns
CF treatment
- The Modulator Drugs
- Respiratory
- Nutrition
Types of CF malfunctioning (Different genes cause the protein defect in different ways)
Type 1
- No protein (nonsense mutation)
Type 2
-No traffic (trafficiking defect) aka gets stuck in endoplasmic retitculum
Type 3
- No function (on cell surface but doesnt work) aka gating effect
Type 4
- Less function (remove some CL) aka gating effect
Type 5
- Less protein (fewer CFTR on cell surface but those that are fully working)
Type 6
- Less stable, last very short times on the cell surface but are fully working
What effect does Modulator Drugs have on the 6 types of mutations
1
Nothing availiable
2
Trikafta (stops wrong folding of protein, takes to cell surface and opens the channel)
3
- ivacaftor
4
- ivacaftor
Management of CF
- History
- Growth
- Enzyme replacement, vitamin supplments, salt supplement, high calorie diet, nurtional supplementation, gastrostomy feeding. - Examination
- finger clubbing, chest deformity, oxygen saturation, resp secretion sampling, lung function tests - Testing
** Chest Physiotherapy
encouraged at least daily AND exercise AND Antibiotics for infection
Options for future children for parents to avoid CF
Preimplantation Genetic Testing (PGT)
- Undergo an IVF cycle to
create multiple eggs,
fertilise the egg
-Biopsy the embryo,
removing ~3-10 cells
for Genetic testing
-Transfer an unaffected embryo
So, now we want to test this
pregnancy- is this fetus affected?
Non Invasive Prenatal
Diagnosis (NIPD)
- Non-invasive prenatal diagnosis uses
circulating cell-free fetal DNA (cffDNA) in the
maternal plasma to test for a known genetic
disease in a family by relative haplotype
dosage analysis (RHDO)
RHDO is a linkage based method, involves
analysis of multiple SNPs which flank the
disease gene
What is cffDNA
- cell types
-size?
- From the placenta (trophoblasts)
- Represents whole fetal genome
- Maternal cfDNA is 166pm, cffDNA 143bp
Benefits of NIPD
- No risk of miscarriage
- Easier sample collection (Blood test vs
invasive prenatal) - Possibility of earlier diagnosis, from 9
weeks gestation (but usually from 11
weeks) - NIPD does NOT require confirmation
invasive test
Challenges of NIPD for CF
- Maternal blood must arrive in the UK within 7 days
- Lab requires DNA from both parents and offspring (either
affected or unaffected) - Possibility of “no result” if low fetal fraction
- No public funding currently in NZ for this EXPENSIVE
