5.5 - Pedigrees and Risk

Question 1

Basic pedigree symbols

Answer 1

• square - male
• circle - female
• filled - affected
• half-filled - carrier (autosomal)
• dot in centre - carrier (X-linked)
• line through - deceased
• arrow - proband (person seeking medical attention)

Question 2

Why draw a pedigree?

Answer 2

• provides a clear simple summary of information
• able to easily spot patterns
• explain pattern to patient
• identify potential carriers of risk gene
• calculate risk of passing on disease / being a carrier
• allows informed choice

Question 3

Why not test for disease gene?

Answer 3

• many diseases are a mix of familial and sporadic - familial means gene based, sporadic means random and non-hereditary
• many causative genes are not known
• impossible to test everyone for disease genes
• when a disease is not exclusively familial and mutation is known many do not want a test e.g. 80% of people with 50% risk of being a carrier for Huntington’s disease decline a test

Question 4

How do you draw a pedigree?

Answer 4

• start at the bottom with the proband and siblings
• choose one parent and ask about their siblings, children and parents
• add the other side of the family
• ask about children of other partners

Question 5

What are potential difficulties of drawing pedigrees?

Answer 5

• incomplete information - e.g. may not have information on all / many relatives
• incorrect information - e.g. family history may not be correct

Question 6

Types of pedigrees - autosomal dominant

Answer 6

• vertical transmission
• not all offspring affected
• males and females affected
• at least one affected parent - can be mother or father
  Why?
• mutated gene interferes with function of normal gene / gains new activity therefore if you have the mutation you have the disease
• both sexes have two of each autosome, so 50% risk of inheritance

Question 7

Types of pedigrees - X-linked (recessive)

Answer 7

• not all generations affected
• not all offspring affected
• only males affected
• inherited from unaffected mother
  Why?
• mutation has no effect on its own
• females: XX and males: XY
• males inherit their X chromosome from their mother
• if mother is a carrier, there is 50% risk of disease (son)

Question 8

Types of pedigrees - mitochondrial

Answer 8

• vertical transmission
• all generations affected
• all offspring affected
• males and females affected
• inherited from affected mother
  Why?
• mutated gene in mitochondrial DNA
• mitochondria inherited from mother
• therefore affected mother = affected child

Question 9

Types of pedigrees - impossible to tell

Answer 9

• no family history
• could be non-genetic
• chromosomal?
• new dominant mutation
• recessive

Question 10

Types of pedigree - autosomal recessive

Answer 10

• usually no family history of disease
• parents unaffected
• horizontal transmission - siblings, cousins affected
• not all offspring affected
• males and females affected
• possible consanguinity in pedigree
• obligate carriers
  Why?
• mutated gene has no effect on own
• therefore having single mutated allele has no effect
• both sexes have two of each autosome, therefore require two mutated copies to express disease

Question 11

What is risk?

Answer 11

• calculation of the predicted chance of having the disease or being a carrier
• work from person with known phenotype to subject
• if more than one affected individual then start with the closest relative on each side of the family
• calculate the risk for each person on path from the start point to the subject - assuming carriers
• multiply risks together
• consider wording of question e.g. if they specifically ask about son/daughter, remember 50% chance of each

Question 12

Risk modifiers

Answer 12

• which side of the family is the disease on? X-linked, mitochondrial
• ethnic background - many diseases have different prevalence in different populations e.g. CF, sickle cell, Tay-Sachs
• consider heterozygote advantage, founder effect
• information you know about the person - their phenotype, their biological sex

Question 13

How do you read pedigrees?

Answer 13

1. who is the condition inherited from?
   - mothers only - mitochondrial
   - fathers only - Y-linked
   - either - move on to Q2
2. can unaffected parents have an affected child? - yes, recessive trait (parents must be heterozygous) OR can affected parents have an unaffected child? - yes, dominant trait (parents must be heterozygous)
3. is there any sex predilection?
   - more common in females - tends to be X-linked dominant (affected male transmits disease only to daughters)
   - more common in males - tends to be X-linked recessive (affected female transmits disease only to sons)
   - no sex predilection - autosomal inheritance