Autosomal recessive inheritance Risks to children where a parent is 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

Question: What are the risks to the children of someone with an autosomal recessive disorder?

Homozygotes with two copies of the altered gene are affected Question: What are the risks to the children of someone with an autosomal recessive disorder? Reminder: Answer: We can deduce these risks by imagining which of the two genes of the parents have been passed on to children as shown on the next few screens Chromosome Gene

Parents AUTOSOMAL RECESSIVE: one parent affected Parents have two copies of autosomal genes: one copy on each of a particular pair of chromosomes

Parents AUTOSOMAL RECESSIVE: one parent affected A parent who is affected by an autosomal recessive disorder has two copies of the altered gene A partner from the general population, who is unrelated, is unlikely to be a carrier for the same disorder, and so will have two copies of the normal gene Affected

Parents Gametes AUTOSOMAL RECESSIVE: one parent affected The affected parent passes on a copy of the altered gene into all of his/her gametes The other parent passes on copies of the normal gene into his/her eggs or sperm Affected

Parents Gametes AUTOSOMAL RECESSIVE: one parent affected There are four different combinations of the two genes from each parent Affected

Parents Gametes Offspring AUTOSOMAL RECESSIVE: one parent affected This child has inherited a copy of the altered gene from the affected parent and a copy of the normal gene from the unaffected parent Affected

Parents Gametes Offspring AUTOSOMAL RECESSIVE: one parent affected This child has inherited the altered gene from the affected parent but the normal gene from the other parent Affected

Parents Gametes Offspring AUTOSOMAL RECESSIVE: one parent affected Affected

Parents Gametes Offspring AUTOSOMAL RECESSIVE: one parent affected This child has inherited the altered gene from the affected parent and the normal gene from the second parent Affected

Parents Gametes Offspring AUTOSOMAL RECESSIVE: one parent affected Affected

Parents Gametes Offspring AUTOSOMAL RECESSIVE: one parent affected This child has inherited the altered gene from the affected parent and a normal gene from the unaffected parent Affected

Parents Gametes Offspring AUTOSOMAL RECESSIVE: one parent affected Which children are affected by the disease? Affected

Parents Gametes AUTOSOMAL RECESSIVE: one parent affected Unaffected carrier Affected

AUTOSOMAL RECESSIVE: one parent affected None of the children of a person affected by an autosomal recessive condition will therefore be affected, as long as the partner is not a carrier for the same condition. All the children will be carriers, but healthy. Occasionally a person with an autosomal recessive disorder has a child affected with the same disorder. This is discussed on the following pages.

When a person with an autosomal recessive condition has a child with the same condition, their unaffected partner must be a carrier for a mutation at the same gene locus. This is rare if the partner is unrelated and from the general population. Where a partner is a carrier for the same recessive disorder, the risk to a child of having the condition is 1 in 2 as shown on the next slide. When a parent and child are affected with the same autosomal recessive condition, the pedigree can be described as showing “pseudo-dominant inheritance”.

Parents Gametes AUTOSOMAL RECESSIVE: one parent affected, other parent a carrier Affected Unaffected carrier Affected

It may be possible by using the Hardy-Weinberg equation p 2 + 2pq + q 2 = 1 and knowledge of the frequency of affected homozygotes (q 2 ) in the particular population. Having calculated the frequency of carriers, this can then be used in genetic counselling to calculate the risk of an affected person having a child affected with the same condition. How do we calculate the probability that someone from the general population is a carrier for the same autosomal recessive disorder?

Occasionally, each parent can be affected by the same autosomal recessive disorder. What are the risks to their children? Affected

Parents Gametes AUTOSOMAL RECESSIVE: both parents affected Affected If the disease in both parents is caused by the same gene, all their children will be affected Affected

Occasionally, each parent can appear to be affected by the same autosomal recessive disorder, but all their children are unaffected. What is the explanation?

Parents Gametes AUTOSOMAL RECESSIVE: both parents affected; genes at different loci Unaffected All are carriers for both disease genes If the disease in both parents is caused by different genes at different loci, all their children will be unaffected Affected

They are important clinically because of the high risks to other family members. Autosomal recessive conditions are part of the group of single gene disorders, which also include autosomal dominant, and X-linked conditions. Chromosome Gene

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