Transcript X-LINKED DOMINANT INHERITANCE: mother affected

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
Reminder:
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.
Hemizygotes (males) with one copy of
the altered gene are affected.
Gene
X-Chromosome
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
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
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
Unaffected
Father
An unaffected male
will have an X
chromosome with a
normal gene and a Y
chromosome
Mother
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
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
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 altered
allele
X
or the X
chromosome
containing
the normal
allele
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
Unaffected
Father
Mother
Gametes
X
Y
X
There are
four different combinations
of the two chromosomes from each
parent
X
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
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
altered gene
Daughter
X
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
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
normal gene
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
Unaffected
Father
Mother
Gametes
X
Y
X
Offspring
Daughter
Daughter
Son
X
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
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 altered gene
Son
X
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
Unaffected
Father
Mother
Gametes
X
Y
X
X
Offspring
Daughter
Daughter
Son
Son
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
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
normal gene
Son
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
Unaffected
Father
Mother
Gametes
X
Offspring
Daughter
Y
X
X
Which children are affected by the disease?
Daughter
Son
Son
X-LINKED DOMINANT INHERITANCE: mother affected
Parents
Affected
Unaffected
Father
Mother
Gametes
X
Affected
female
Daughter
Y
Unaffected
female
Daughter
X
Affected
male
Son
X
Unaffected
male
Son
X-LINKED DOMINANT INHERITANCE: mother 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 ).
Where the father is affected by
an X-linked dominant disorder
X-LINKED DOMINANT INHERITANCE: father affected
Parents
Affected
Father
Mother
Gametes
X
Offspring
Daughter
Y
X
X
Which children are affected by the disease?
Daughter
Son
Son
X-LINKED DOMINANT INHERITANCE: father affected
Parents
Affected
Father
Mother
Gametes
X
Affected
female
Daughter
Y
Affected
female
Daughter
X
X
Unaffected
male
Unaffected
male
Son
Son
Here is another family with pedigree
features which suggest an X-linked
dominant disorder. What are they?
I:1
Frank
Bradley
II:1
Philip
Ward
III:1
Patricia
III:2
Victoria
II:2
Mary
III:3
William
IV:1
Gavin
IV:2
Alice
I:2
Edith
II:3
Joan
III:4
Alison
III:5
Lauren
IV:3
Sinead
II:4
William
Severn
III:6
Wayne
II:5
Jayne
III:7
Sharon
III:8
Jason
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)
III:1
Patricia
I:1
Frank
Bradley
II:1
Philip
Ward
III:2
Victoria
II:2
Mary
III:3
William
IV:1
Gavin
IV:2
Alice
I:2
Edith
II:3
Joan
III:4
Alison
III:5
Lauren
IV:3
Sinead
II:4
William
Severn
III:6
Wayne
II:5
Jayne
III:7
Sharon
III:8
Jason
Examples of X-linked dominant disorders
X-linked dominant disorders are relatively uncommon
compared with disorders inherited by the other modes of
Mendelian inheritance
Males more severely affected than females
Vitamin D-resistant rickets
Condition causing lethality in males
Goltz syndrome
X-linked dominant
conditions are part of the
group of single gene
disorders, which also
include autosomal
dominant, autosomal
recessive, and X-linked
recessive.
They are important
clinically because of
the high risks to other
family members.
Gene
X-Chromosome
Pedigrees demonstrating X-linked dominant or mitochondrial
inheritance can look similar: look for particular clues from the
pedigree
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.
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