1. X-linked recessive inheritance where the father is affected: the basics a tutorial to show how the genes segregate to give the typical pedigree pattern Professor P Farndon, Clinical Genetics Unit, Birmingham Women’s Hospital 13.11.06

2. Question: How can one understand the risks of an X- linked recessive condition where a father is affected? I:1I:2 II:2II:1II:3 III:2III:3III:4III:1 IV:1IV:2

3. Hemizygotes (males) with one copy of the altered gene are affected Question: How can one understand the risks of an X- linked recessive condition where a father is affected? Reminder: Answer: By imagining which of the sex chromosomes of the parents have been passed on to children as shown on the next few screens X-Chromosome Gene

4. Humans have 23 pairs of chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes Male karyotype Female karyotype

5. The male sex chromosomes: an X and a Y The female sex chromosomes: two X chromosomes

6. Parents X-LINKED RECESSIVE INHERITANCE: father affected FatherMother Affected An affected male will have an X chromosome with a altered gene and a Y chromosome A woman who is not a carrier of an X- linked recessive disorder has two copies of the normal gene - one on each X chromosome

7. Parents Gametes FatherMother XYXX Affected The father passes on either his X chromosome containing the altered gene or his Y chromosome (and so determines the sex of the fetus) The mother passes on one or the other of her X chromosomes (both with normal genes) X-LINKED RECESSIVE INHERITANCE: father affected

8. Parents Gametes FatherMother XYXX Affected There are four different combinations of the two chromosomes from each parent X-LINKED RECESSIVE INHERITANCE: father affected

9. Parents Gametes Offspring FatherMother XYXX Daughter Affected This child has inherited the paternal X chromosome with the altered gene (and so is female) and the maternal X chromosome with the normal gene X-LINKED RECESSIVE INHERITANCE: father affected

10. Parents Gametes Offspring FatherMother XYXX Daughter Affected This child has inherited the paternal X chromosome with the altered gene (and so is female) and the other maternal X chromosome with a normal gene X-LINKED RECESSIVE INHERITANCE: father affected

11. Parents Gametes Offspring FatherMother XYXX Daughter Son Affected X-LINKED RECESSIVE INHERITANCE: father affected

12. Parents Gametes Offspring FatherMother XYXX Affected This child has inherited the paternal Y chromosome (and so is male) and a maternal X chromosome with a normal gene Son X-LINKED RECESSIVE INHERITANCE: father affected

13. Parents Gametes Offspring FatherMother XYXX Daughter Son Affected X-LINKED RECESSIVE INHERITANCE: father affected

14. Parents Gametes Offspring FatherMother XYXX Son Affected This child has inherited the paternal Y chromosome (and so is male) and the other maternal X chromosome with a normal gene X-LINKED RECESSIVE INHERITANCE: father affected

15. Parents Gametes Offspring FatherMother XYXX Daughter Son Affected Which children are affected by the disease? X-LINKED RECESSIVE INHERITANCE: father affected

16. Parents Gametes FatherMother XYXX Daughter Son Unaffected carrier Unaffected male Affected Unaffected carrier Unaffected male X-LINKED RECESSIVE INHERITANCE: father affected

17. All the children of a male with an X-linked recessive disorder are therefore unaffected by his X-linked disease. All his daughters will be carriers. Their sons will inherit either the X-chromosome with the normal gene or the X- chromosome with the altered gene. X-LINKED RECESSIVE INHERITANCE: father affected

18. Examples of X-linked recessive diseases Fragile X syndrome 5 Non-specific X-linked mental retardation 5 Duchenne muscular dystrophy 3 Becker muscular dystrophy 0.5 Haemophilia A (factor VIII) 2 Haemophilia B (factor IX) 0.3 UK frequency / 10,000 males

19. They are important clinically because of the high risks to other family members. X-linked recessive conditions are part of the group of single gene disorders, which also include autosomal dominant and recessive disorders. X-Chromosome Gene

20. The end ! Thank you for completing this revision aid We are interested in your comments about this aid. Please email Professor Farndon. (p.a.farndon@bham.ac.uk) © P Farndon 2003