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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
Question:How can one relate an X-linked dominant pedigree pattern to the segregation of genes at meiosis?
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
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.
What are the pedigree features which would suggest an X-linked dominant disorder?
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
Parents
X-LINKED DOMINANT INHERITANCE: mother affected
Father Mother
AffectedUnaffected
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
Parents
Gametes
Father Mother
X Y XX
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
Parents
Gametes
Father Mother
X Y XX
Unaffected
There are
four different combinations
of the two chromosomes from each parent
X-LINKED DOMINANT INHERITANCE: mother affected
Affected
Parents
Gametes
Offspring
Father Mother
X Y XX
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
Parents
Gametes
Offspring
Father Mother
X Y XX
Daughter 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
Parents
Gametes
Offspring
Father Mother
X Y XX
Daughter Daughter Son
Unaffected
X-LINKED DOMINANT INHERITANCE: mother affected
Affected
Parents
Gametes
Offspring
Father Mother
X Y XX
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
Parents
Gametes
Offspring
Father Mother
X Y XX
Daughter Daughter Son Son
Unaffected
X-LINKED DOMINANT INHERITANCE: mother affected
Affected
Parents
Gametes
Offspring
Father Mother
X Y XX
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
Parents
Gametes
Offspring
Father Mother
X Y XX
Daughter Daughter Son Son
Unaffected
Which children are affected by the disease?
X-LINKED DOMINANT INHERITANCE: mother affected
Affected
Parents
Gametes
Father Mother
X Y XX
Daughter Daughter Son Son
Unaffected
female
Unaffected male
Unaffected
Affected female
Affected male
X-LINKED DOMINANT INHERITANCE: mother affected
Affected
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
Where the father is affected by an X-linked dominant disorder
Parents
Gametes
Offspring
Father Mother
X Y XX
Daughter Daughter Son Son
Affected
Which children are affected by the disease?
X-LINKED DOMINANT INHERITANCE: father affected
Parents
Gametes
Father Mother
X Y XX
Daughter Daughter Son Son
Affected female
Unaffected male
Affected
Affected female
Unaffected male
X-LINKED DOMINANT INHERITANCE: father affected
Here is another family with pedigree features which suggest an X-linked dominant disorder. What are they?
I:1Frank
Bradley
I:2Edith
II:2Mary
II:1PhilipWard
II:3Joan
II:4WilliamSevern
II:5Jayne
III:4Alison
III:6Wayne
III:7Sharon
III:5Lauren
III:1Patricia
III:2Victoria
III:3William
IV:1Gavin
IV:2Alice
IV:3Sinead
III:8Jason
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)
I:1Frank
Bradley
I:2Edith
II:2Mary
II:1PhilipWard
II:3Joan
II:4WilliamSevern
II:5Jayne
III:4Alison
III:6Wayne
III:7Sharon
III:5Lauren
III:1Patricia
III:2Victoria
III:3William
IV:1Gavin
IV:2Alice
IV:3Sinead
III:8Jason
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
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
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
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 2003
