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

Question: How can one relate an X-linked recessive pedigree pattern to the segregation of genes at meiosis?

Hemizygotes (males) with one copy of the altered gene are affected Question: How can one relate an X-linked recessive pedigree pattern to the segregation of genes at meiosis? 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

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

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

Parents X-LINKED INHERITANCE: mother a carrier FatherMother Carrier Unaffected An unaffected male will have an X chromosome with a normal gene and a Y chromosome A woman who is a carrier of an X- linked recessive disorder has one copy of a normal gene and one copy of an altered gene of the particular pair

Parents Gametes X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Carrier Unaffected 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 normal allele or the X chromosome containing the altered allele

Parents Gametes X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Carrier Unaffected There are four different combinations of the two chromosomes from each parent

Parents Gametes Offspring X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Daughter Carrier Unaffected This child has inherited the paternal X chromosome (and so is female) and the maternal X chromosome with the normal gene

Parents Gametes Offspring X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Daughter Carrier Unaffected This child has inherited the paternal X chromosome (and so is female) and the maternal X chromosome with the altered gene

Parents Gametes Offspring X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Daughter Son Carrier Unaffected

Parents Gametes Offspring X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Carrier Unaffected This child has inherited the paternal Y chromosome (and so is male) and the maternal X chromosome with the normal gene Son

Parents Gametes Offspring X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Daughter Son Carrier Unaffected

Parents Gametes Offspring X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Son Carrier Unaffected This child has inherited the paternal Y chromosome (and so is male) and the maternal X chromosome with the altered gene

Parents Gametes Offspring X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Daughter Son Carrier Unaffected Which children are affected by the disease?

Parents Gametes X-LINKED INHERITANCE: mother a carrier FatherMother XYXX Daughter Son Unaffected carrier Affected male Carrier Unaffected Unaffected female Unaffected male

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 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. “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.” However, we usually explain the risks like this:

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

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

The end ! Thank you for completing this revision aid We are interested in your comments about this aid. Please Professor Farndon. © P Farndon 2001