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X-linked recessive inheritance where the mother is a carrier: 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 Question: How can one relate an X-linked recessive pedigree pattern to the segregation of genes at meiosis? I:1 John Hodgkin II:1 Peter Smith III:1 Andrew Cox IV:1 Jason III:2 Jean IV:2 Duane II:2 Kathleen III:3 Paul Smith I:2 Celia II:3 Gerald III:4 Kevin Smith Question: How can one relate an X-linked recessive 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 as shown on the next few screens Gene Reminder: Hemizygotes (males) with one copy of the altered gene are affected X-Chromosome Male karyotype Female karyotype Humans have 23 pairs of chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes The male sex chromosomes: an X and a Y The female sex chromosomes: two X chromosomes X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father An unaffected male will have an X chromosome with a normal gene and a Y chromosome Mother A woman who is a carrier of an Xlinked recessive disorder has one copy of a normal gene and one copy of an altered gene of the particular pair X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X The father passes on either his X chromosome Y or his Y chromosome (and so determines the sex of the fetus) X The mother passes on either the X chromosome containing the normal allele X or the X chromosome containing the altered allele X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Y X There are four different combinations of the two chromosomes from each parent X X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Y X Offspring This child has inherited the paternal X chromosome (and so is female) and the maternal X chromosome with the normal gene Daughter X X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Y X X Offspring Daughter Daughter This child has inherited the paternal X chromosome (and so is female) and the maternal X chromosome with the altered gene X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Y X Offspring Daughter Daughter Son X X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Y X Offspring This child has inherited the paternal Y chromosome (and so is male) and the maternal X chromosome with the normal gene Son X X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Y X X Offspring Daughter Daughter Son Son X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Y X X Offspring This child has inherited the paternal Y chromosome (and so is male) and the maternal X chromosome with the altered gene Son X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Offspring Daughter Y X X Which children are affected by the disease? Daughter Son Son X-LINKED INHERITANCE: mother a carrier Parents Carrier Unaffected Father Mother Gametes X Unaffected female Daughter Y Unaffected carrier Daughter X Unaffected male Son X Affected male Son X-LINKED INHERITANCE: mother a carrier One has to be very careful in explaining these risks to couples where the woman is a carrier for an X-linked disorder to avoid potential confusion. If the sex of the fetus is unknown, there is a 1 in 4 chance (25%) that he will be both male and affected. X-LINKED INHERITANCE: mother a carrier However, we usually explain the risks like this: “If you have a girl, she has a 1 in 2 chance (50%) of being a carrier “ (and usually completely asymptomatic). “If you have a boy, he has a 1 in 2 chance (50%) of being affected.” Parents will often wish to have prenatal diagnosis by fetal sexing for serious X-linked recessive disorders, and so will want to know the sex of the fetus. Examples of X-linked recessive diseases UK frequency / 10,000 males 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 X-linked recessive conditions are part of the group of single gene disorders, which also include autosomal dominant and recessive disorders. They are important clinically because of the high risks to other family members. Gene X-Chromosome The end! • Thank you for completing this revision aid • We are interested in your comments about this aid. Please email Professor Farndon. ([email protected]) © P Farndon 2001