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 Chromosome Gene Reminder: Heterozygotes with one copy of the altered gene are affected

AUTOSOMAL DOMINANT: Both parents affected Parents have two copies of autosomal genes: one copy on each of a particular pair of chromosomes

AUTOSOMAL DOMINANT: Both parents affected It is very rare that the other parent has the same autosomal dominant disease - (but can occur - for example with achondroplasia or hypercholesterolaemia) A parent with an autosomal dominant disorder has one copy of an altered gene and one normal gene of the particular pair

AUTOSOMAL DOMINANT: Both parents affected Gametes This affected parent passes on either the altered or the normal gene into the eggs or sperm The affected parent passes on either the altered gene or the normal gene into the eggs or sperm

AUTOSOMAL DOMINANT: Both parents affected Gametes There are four different combinations of the two genes from each parent

AUTOSOMAL DOMINANT: Both parents affected 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 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 Gametes Offspring

AUTOSOMAL DOMINANT: Both parents affected 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 Gametes Offspring

AUTOSOMAL DOMINANT: Both parents affected Gametes Offspring This child has inherited the normal gene from the first affected parent and the normal gene from the second affected parent

Which children are affected by the disease? AUTOSOMAL DOMINANT: Both parents affected Parents Gametes Which children are affected by the disease? Offspring

AUTOSOMAL DOMINANT: Both parents affected 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 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. Chromosome Gene They are important clinically because of the high risks to other family members.

The end! Thank you for completing this revision aid We are interested in your comments about this aid. Please email Professor Farndon. (p.a.farndon@bham.ac.uk) © P Farndon 2003