Pedigree Risk Assessment

What are the functions of a pedigree?

• First step risk assessment – visualisation  

• Efficient manner to document family history

• Rapport building  

• Can reveal psychosocial issues  

What are the features of tree symbols?

Provides consistency

What can the challenges with pedigree trees be?

• Require biological relationships 

• Depends on biological sex, sperm donor etc   

What are the features of autosomal dominant inheritance?

• Vertical inheritance pattern with multiple generations affected  

• Each affected person normally has one affected parent  

• Each child has an affected person has ½ chance of inheriting variant  

• Males and females are equally likely to be affected  

• Can be dominant and de novo rather than inherited  

What inheritance is this?

Autosomal dominance

What are the features of autosomal recessive inheritance?

• Horizontal pattern of inheritance, one or more siblings affected, usually no family history  

• Parents and children of affected individuals are usually unaffected  

• Each subsequent sibling of an affected child has a ¼ chance of being affected  

• Males and females are equally likely to be affected  

• May see affected individuals in multiple generations  

What type of inheritance is this?

Autosomal recessive

What are the features of X-linked inheritance?

• Recessive X linked has knights move pattern  

• Affected males may have affected uncles  

• Parents and children of affected individuals are normally unaffected  

• No father to son transmission but all daughters of affected males will be heterozygous carriers  

• Affects mainly males if recessive but females' carriers may present with milder symptoms  

• Can be de novo or dominant X linked condition 

What type of inheritance is this?

X-Linked Recessive

What is penetrance?

TWhahe proportion of individuals with a genetic variant who show features of the condition

What can penetrance depend on?

Age

What is expressivity?

The variation of phenotypic features seen between individuals  

What is an example of expressivity with BRCA1/2?

Can cause breast, ovarian, both or neither types of cancer

What are the features of mitochondrial inheritance?

• Vertical inheritance pattern  

• Children of affected males are never affected  

• All children of an affected woman will be affected but extremely variable  

• Heteroplasmy – depends on the degree of mitochondria that carry the change  

What type of inheritance is this?

Mitochondrial

What type of inheritance is this?

Autosomal dominant

What is the risk?

• A has a low population risk as neither parents have the copy  

• B and C both have a 50% chance that they have affected child  

What is the risk?

Sarah has 50% inheritance chance of developing it as wouldn’t be expected to show symptoms at that stage 

What are the features of Huntington’s?

• Huntington’s is a neurodegenerative condition that demonstrates anticipation  

• The repeat gets larger as passed between generations and important when it borders 

• Doesn't always gets larger by the same amount  

• Has age related penetrance  

What is the risk?

• Sarah had a 50% chance of developing it and died before presentation so don’t know if she has it  

• Means that you half the chance for the offspring so Rob has 25% chance  

What are the features of Friedreich Ataxia?

• Ataxia is loss of balance, difficulty walking, unsteady  

• Nerve dysfunction loss of muscle coordination, weakness in legs, loss of sensations  

• Speech and swallowing changes  

• Systemic complications, diabetes, hearing loss etc  

What is the risk?

• Has a ¼ chance of being affected as each parent is a carrier but needs two copies  

• Has ½ chance of being a carrier  

• 2/3 chance as you know she doesn’t have both copies so only 3 possible options and 2 are carriers  

What is the risk of the baby being affected?

1/150

Which of these people would be carriers?

What are the features of consanguineous marriages?

• Consanguinity may not be noted  

• Both parents of unaffected child could be carriers  

• More common in families from a small region  

What is the risk to the pregnancy?

How are X-linked disorders inherited?

• Affected females will have affected sons, healthy sons and daughters or carrier daughters  

• Affected males will have female carriers and unaffected sons  

What is the risk?

What are the features of the Hardy-Weinberg Principle?

• Used for carrier frequencies  

• Used for recessive conditions  

• The allele frequency in a population will remain constant in the absence of evolutionary influences  

• A is affected and a is recessive 

What are the Hardy-Weinberg equations?

What is the risk?

How is HW used with consanguinity?

• Can not be assumed to work with consanguinity  

• If most cases of rare recessive conditions occur in consanguineous families the Hardy-Weinberg equation can’t be applied  

• Will badly over-estimate the frequency of carriers in the general population 

What are the features of Bayes theory?

• Combines risk information from different sources  

• Modifies the probability of an outcome based on conditional probabilities  

• Works out a prior risk  

• Ask what additional information is available  

• Test results  

• Penetrance  

• Unaffected children / siblings  

• Works out the conditional probability  

How does Bayes work?

What is the risk?