Transcript Both parents affected

Autosomal dominant inheritance
Risks to children where both
parents are affected: 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:
What are the risks to children if both parents
are affected by the same autosomal
dominant condition?
Question:
What are the risks to children if both parents
are affected by the same autosomal
dominant condition?
Answer:
By determining the different
combinations of the genes of the
parents which can be passed on to
children as shown on the next few
screens
Gene
Reminder:
Heterozygotes with one copy of the
altered gene are affected
Chromosome
AUTOSOMAL DOMINANT: Both parents affected
Parents
Parents have two copies of autosomal genes:
one copy on each of a particular pair of
chromosomes
AUTOSOMAL DOMINANT: Both parents affected
Parents
A parent with an
autosomal dominant
disorder has one copy of
an altered gene and one
normal gene of the
particular pair
It is very rare that
the other parent
has the same
autosomal
dominant disease
- (but can occur - for
example with
achondroplasia or
hypercholesterolaemia)
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
The affected
parent passes
on either the
altered gene
or the normal
gene into the
eggs or sperm
This affected
parent passes on
either the altered
or the normal
gene into the eggs
or sperm
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
There are
four different combinations
of the two genes from each parent
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Offspring
This child has inherited the altered
gene from the first affected parent
and the altered gene from the other
affected parent
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Offspring
This child has inherited the
altered gene from the affected
parent but the normal gene
from the other affected parent
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Offspring
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Offspring
This child has inherited the
normal gene from the first
parent and the altered
gene from the second
affected parent
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Offspring
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Offspring
This child has inherited
the normal gene from the
first affected parent and
the normal gene from the
second affected parent
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Offspring
Which children are affected by the disease?
AUTOSOMAL DOMINANT: Both parents affected
Parents
Gametes
Affected
Affected
Affected
Unaffected
AUTOSOMAL DOMINANT: Both parents affected
Each child of a couple who both have an autosomal
dominant disorder therefore has a
1/4 chance of being
homozygous for the
disease gene
1/2 chance of being a
heterozygote for the
disease
1/4 chance of being
homozygous normal
The clinical effects of homozygosity for an autosomal
dominant disorder
Most autosomal dominant disorders occur only in the heterozygous state
because the disorder is relatively rare in the population.
For some conditions, being homozygous for the dominant disorder causes the
individual to be more severely affected (as in achondroplasia) or for the
disorder to have an earlier age of onset (eg familial hypercholesterolaemia).
In other disorders, for instance Huntington disease, homozygotes appear to
have an indistinguishable clinical course from patients who are heterozygous
for the mutant gene.
The difference may depend on how the nature of the mutation affects the gene
product. For instance, conditions where the heterozygote has clinical features
intermediate between homozygous normal and homozygous affected seem to
be associated with alleles which stop a gene product from being produced.
The heterozygotes are postulated to have half the normal concentration of the
gene product whilst homozygous affected individuals make none.
Occasionally, each parent can be affected by a
different dominant disorder.
What are the risks to their children?
AUTOSOMAL DOMINANT: both parents affected; genes at different loci
Parents
Gametes
Affected by
both disorders
Affected by
first disorder
Affected by
second disorder
Unaffected
Autosomal dominant
conditions are part of the
group of single gene
disorders, which also
include autosomal
recessive, and X-linked
conditions.
They are important
clinically because of
the high risks to other
family members.
Gene
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 2003