1. X-linked inheritance
Oliver Quarrell

2. Lecture Plan Lyon hypothesis X linked recessive males do not reproduce
X linked recessive males reproduce
X linked dominant
X linked dominant lethal in males
Main example will be Duchenne muscular dystrophy
Options for a female carrier

5. Sex-linked inheritance
Genes carried on the X chromosome.
More males than females affected.
Females are carriers. 50% sons affected. 50% daughters are carriers.
All daughters of affected males are carriers.
None of the offspring of affected males have the disorder.
Possibility of new mutations.
Gonadal mosaicism may occur.
Influenced by X inactivation.

6. Lyon hypothesis X-chromosome inactivation
Occurs early in embryogenesis
Random process
Once occurred cells from subsequent cell divisions inactivate the same X-chromosome
There are some rare mechanisms which result in non-random X-inactivation

7. X-Linked Inheritance X X X Y

8. Muscular dystrophy
“please see this lady who has a relative affected by muscular dystrophy”
WHICH ONE
Beware of umbrella terms
In this lecture we are focusuing on the x-linked forms Duchenne and Becker
Comment on NHS choices website

9. Scenario A lady presents to ante-natal clinic
Her brother had Duchenne muscular dystrophy
Her uncle died of muscular dystrophy age 21 he was in wheelchair.
Her mother must be a carrier

10. Summary of clinical problem

11. www.neuro.wustl.edu/.../ pathol/dmdpath.htm

12. www.neuro.wustl.edu/.../ pathol/dmdpath.htm

13. www.mja.com.au/.../ byr10494_fm.html

15. Gower’s Sign
Proximal muscle weakness
Have to climb up legs

16. Duchenne Muscular dystrophy
Affects males
May have delayed walking or running
Progressive weakness – waddling gait
Treatment steroids and later ventilatory support
Wheelchair
Die of respiratory failure
Do not reproduce
Raised creatine kinase muscle enzyme
70% deletion in dystrophin gene

17. What is the chance of an affected son?

18. Management
Normal CK reduces chance of her being carrier but does not exclude it LYONISATION
Identify deletion in brother test pregnant lady
Look for point mutation

19. New mutations Males do not reproduce
To maintain prevalence in population need new mutations
In an isolated case 1/3 cases are new mutations
Consider an isolated case

21. Clinical Problem May be a new mutation Mother may be a carrier
May be gonadal mosaicism
Sister may or may not be a carrier
Daughter may or may not be a carrier

22. Management Normal CK of limited value
70% chance of identifying deletion in boy
Rises to over 90% point mutations
If mother not a carrier cannot exclude gonadal mosaicism
Residual risk to daughter

23. May be gonadal mosaicism No need to test sister
Deletion absent
Deletion present
May be gonadal mosaicism No need to test sister
But offer carrier test to daughter when she is 16 +

24. Primordial germ cell
Egg

25. Mother is a carrier have to offer to test mother and sister
Deletion present
Deletion present
Mother is a carrier have to offer to test mother and sister
Offer carrier test to daughter when she is 16 +

26. New scenario daughter is a carrier. What are her options?
Deletion present
Deletion present
Deletion present

27. Options for a carrier female
Not have any children
Accept the risk and have children
Have a blood sample at 7-9 weeks for free fetal DNA
Have pre-natal diagnosis (PND) and consider TOP of affected male fetus
Consider pre-implantation genetic diagnosis PGD

28. Prenatal diagnosis Option of free fetal DNA at 9 weeks
Some genetic material from the fetus circulates in the mother blood.
If Y chromosome material assume it is male
If no Y chromosome material assume it is female
Error rate less than 1%

29. Invasive test Chorion biopsy From 11 weeks
Take sample from placental bed
Risk of misc ~ 1- 2%
Can do an amniocentesis but from 15 weeks and have to grow the cells
Risk misc ~1%

30. Chorion Biopsy

32. Success rate at outset 20%
Success rate at embryo transfer
~30%

33. What happens if male can reproduce
Becker Muscular dystrophy
Haemophilia A or B

34. www.neuro.wustl.edu/.../ pathol/dmdpath.htm

36. X-Linked Inheritance X X X Y C C C

37. X-linked dominant
What happens to females if the condition is X-linked dominant?

38. What happens if the mutation is extremely deleterious
X-linked dominant lethal in males
Males die in utero
Females survive because they are mosaics

39. X chromosome and disease in females
Fragile X
Affected females
Intellectual impairment
DMD
Most carriers
Normal IP
Retts
Lethal in most males

40. Incontinentia Pigmenti
X-linked dominant lethal in males
Can see the Lyonisation

41. Sex-linked inheritance
Genes carried on the X chromosome.
More males than females affected.
Females are carriers. 50% sons affected. 50% daughters are carriers.
All daughters of affected males are carriers.
None of the offspring of affected males have the disorder.
Possibility of new mutations.
Gonadal mosaicism may occur.
Influenced by X inactivation.