1. X-linked dominant inheritance: 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 relate an X-linked dominant pedigree pattern to the segregation of genes at meiosis?

3. Question: How can one relate an X-linked dominant pedigree pattern to the segregation of genes at meiosis? Answer: By imagining which of the sex chromosomes of the parents have been passed on to children Father Mother

4. X-Chromosome Gene Reminder: Hemizygotes (males) with one copy of the altered gene are affected. In X-linked dominant disorders, the male will be more severely affected than the female. For some conditions, the disorder is so severe that males die before birth Heterozygotes (females) with one copy of the altered gene are affected in X-linked dominant disorders. In each cell of a female, either the paternally or maternally inherited X chromosome has been inactivated at random. This ensures that the concentrations of gene products from the X chromosome are the same as in a male. Females affected by an X-linked dominant disorder are therefore usually less severely affected than males because the disease gene is not active in every cell.

5. What are the pedigree features which would suggest an X-linked dominant disorder?

6. Dominant: In each generation (“vertical transmission”) Affected people have affected and unaffected children X-linked: Half of female children of affected females affected Half of male children of affected females affected No sons of affected men affected All daughters of affected men affected

7. Parents X-LINKED DOMINANT INHERITANCE: mother affected FatherMother Affected Unaffected An unaffected male will have an X chromosome with a normal gene and a Y chromosome A woman who has an X-linked dominant disorder has one copy of an altered gene and one copy of a normal gene of the particular pair

8. Parents Gametes FatherMother XYXX Unaffected Affected The father passes on either his X chromosome or his Y chromosome (and so determines the sex of the fetus) The mother passes on either the X chromosome containing the altered allele or the X chromosome containing the normal allele X-LINKED DOMINANT INHERITANCE: mother affected

9. Parents Gametes FatherMother XYXX Unaffected There are four different combinations of the two chromosomes from each parent X-LINKED DOMINANT INHERITANCE: mother affected Affected

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

11. Parents Gametes Offspring FatherMother XYXX Daughter Unaffected This child has inherited the paternal X chromosome (and so is female) and the maternal X chromosome with the normal gene X-LINKED DOMINANT INHERITANCE: mother affected Affected

12. Parents Gametes Offspring FatherMother XYXX Daughter Son Unaffected X-LINKED DOMINANT INHERITANCE: mother affected Affected

13. Parents Gametes Offspring FatherMother XYXX Unaffected This child has inherited the paternal Y chromosome (and so is male) and the maternal X chromosome with the altered gene Son X-LINKED DOMINANT INHERITANCE: mother affected Affected

14. Parents Gametes Offspring FatherMother XYXX Daughter Son Unaffected X-LINKED DOMINANT INHERITANCE: mother affected Affected

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

16. Parents Gametes Offspring FatherMother XYXX Daughter Son Unaffected Which children are affected by the disease? X-LINKED DOMINANT INHERITANCE: mother affected Affected

17. Parents Gametes FatherMother XYXX Daughter Son Unaffected female Unaffected male Unaffected Affected female Affected male X-LINKED DOMINANT INHERITANCE: mother affected Affected

18. When explaining the risks to couples where the woman has an X-linked dominant disorder one can say (if the disease is not lethal in males) that there is a 1 in 2 chance that each child will be affected (regardless of the child’s sex ). X-LINKED DOMINANT INHERITANCE: mother affected

19. Where the father is affected by an X-linked dominant disorder

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

21. Parents Gametes FatherMother XYXX Daughter Son Affected female Unaffected male Affected Affected female Unaffected male X-LINKED DOMINANT INHERITANCE: father affected

22. Here is another family with pedigree features which suggest an X-linked dominant disorder. What are they?

23. Dominant: In each generation (“vertical transmission”) Affected people have affected and unaffected children X-linked: Only females affected Half of female children affected Half the number of males expected in the children of affected women (suggesting that the condition is so severe in males that it is lethal)

24. Examples of X-linked dominant disorders Vitamin D-resistant rickets Males more severely affected than females Condition causing lethality in males Goltz syndrome X-linked dominant disorders are relatively uncommon compared with disorders inherited by the other modes of Mendelian inheritance

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

26. In X-linked dominant inheritance each son and daughter of an affected woman has a one in two chance of inheriting the X-chromosome which has the disease gene and so being affected. all the daughters of an affected man are affected because they all inherit his single X chromosome on which is located the disease gene. All his sons are unaffected. A pedigree caused by mitochondrial inheritance (ie due to a mutation in the DNA in the mitochondria rather than a mutation in the nuclear DNA) classically shows all the children (male and female) of an affected woman are affected. None of the children of an affected man are affected because mitochondria are not transmitted in sperm. Pedigrees demonstrating X-linked dominant or mitochondrial inheritance can look similar: look for particular clues from the pedigree

27. 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