Transcript X-linked recessive inheritance where the mother is a carrier

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