X linked Flashcards
X linked recessive inheritance
Females (46,XXh) are carriers (heterozygous) and are typically unaffected
usually transmit to sons with a 50% chance
50% chance that daughters will be carriers
Affected males will ALWAYS give to daughters but never to sons
Examples of X linked recessive disorders
- Haemophilia
- Colour blindness
- Muscular dystrophy
- Fragile X syndrome
What is haemophilla deficency in
factor 8 and 9
affects MALES
Clinical signs of haemophilla
Recurrent and spontaneous bleeding at
Joints
Soft tissues
muscle
other sites: CNS
Managment of haemophilla
Infusions of coagulation
factor
* Treatment of acute bleeding
* Prophylaxis to prevent
bleeding
Adequate pain relief
Rest of affected joint
2 diagnostic methods of X
linked recessive disorders
- Examine family tree to give probabilities
- Phenotypic Analysis
clotting factor levels in blood
- Normal factor VIII levels 50 – 150 u/L (%)
- Severe haemophilia factor levels <1%
- Female carrier levels approx 50% due to Lyonisation
If females are 46, XX; why do they not produce twice as much protein for any X
chromosome encoded gene eg coagulation
factor VIII ?
Due to random inactivation of one X chromosome in somatic cells; inactive X =
Barr body; occurs early at approx day 16 of
embryo development
Issues with phenotypic
analysis in X linked disorders
Factor VIII and IX levels can be used to diagnose females who are carriers / heterozygous XhX but…
-Variation in normal clotting factor levels
eg with exercise, stress etc
-Requires fetal blood sample for prenatal
diagnosis, therefore late and difficult
Genetic disease analysis Diagram
- samples
-sample type
-purpose
Blood, Skin, CVS and amnoitic fluid all have DNA which is anaylsed in polymorphic linkage or direct mutation detection
LEADING TO
diagnosis of female carriers and PRENATAL diagnosis
Mutations causing Haemophilia
Mutation in genes of Factor 8 or 9
* Structural changes eg deletions
* Point mutations
Types of mutation anaylsis
Direct:
* Analyze DNA from affected patient –identify mutation
* Potential female carriers eg sister of a
haemophilia patient – can accurately confirm
carrier status
Indirect:
* If mutation in family not known can use linked polymorphic markers / single nucleotide polymorphisms (SNPs) to track the abnormal gene in a family
What does linkage anaylsis use
- common site targeted?
- RFLPs
– restriction fragment length
polymorphisms - VNTRs
– variable number tandem repeats
Bcl I
Problems with linkage analysis
- Requirement for family studies
including availability of index case - Non-paternity
- Recombination
- Lack of an informative
marker / polymorphism
Options for female confirmed as carrier for prenatal diagnosis
Mutation analysis of fetal DNA obtained by
chorionic villous biopsy or amniocentesis
In vitro fertilization followed by analysis of
6-8 cell blastocyst:
– Select non male embryos
– Select embryos with normal factor 8 gene
Medicine for Haemophilla people
Recombinant factor VIII and IX
– Removes risk of transfusion transmitted
infection, safer
Describe Gene therapy process
- DNA that encodes factor 8 or 9
2.insert into virus - enters liver and new factors made
