07 Pedigrees and Risk Calculation

Question 1

What are some good reasons to draw a pedigree?

Answer 1

It’s the first step of genetic risk assessment.
It’s easy to visualise.
It’s an efficient way to collect family history.
It builds rapport.
It can reveal psychosocial issues such as comms barriers in the family.

Question 2

What does a slash mean in a pedigree?

Answer 2

Someone is deceased

Question 3

What does a shaded in shape mean in a pedigree?

Answer 3

An affected family member

Question 4

What does a square mean in a pedigree?

Answer 4

A male

Question 5

What does a circle mean in a pedigree?

Answer 5

A female

Question 6

How would you draw a fetus of unknown sex in a pedigree?

Answer 6

A diamond and say how many weeks old

Question 7

How would you draw a stillbirth on a pedigree?

Answer 7

Either a diamond, square or circle, with a slash through it, and the letters SB.

Question 8

How would you draw the distinction between a termination of pregnancy and a miscarriage/spontaneous abortion on a pedigree?

Answer 8

A termination of a pregnancy is with a slash. A miscarriage or spontaneous abortion has no slash. Both would be triangles.

Question 9

What is a dot inside a shape on a pedigree?

Answer 9

A carrier

Question 10

What does it mean when sections of a shape are shaded in?

Answer 10

Different aspects of the phenotype. Maybe Ovarian OR breast cancer.

Question 11

How are fraternal and identical twins differentiated on a pedigree?

Answer 11

Both sets are draw with diagonal lines going down. Identical twins have a horizontal line between them connecting them, fraternal do not.

Question 12

How are asymptomic/presymptomatic carriers drawn on a pedigree?

Answer 12

A horizontal line down through the middle of the shape.

Question 13

How are consanguinous couples shown on a pedigree?

Answer 13

two horizontal lines connecting them.

Question 14

What do you often put on a pedigree next to each person’s icon?

Answer 14

DOB and name

Question 15

What generally causes an autosomal recessive inheritance?

Answer 15

A biallelic LOF

Question 16

What pattern do AR disorders show on a pedigree?

Answer 16

Horizontal pattern - siblings affected, neither parent

Question 17

What’s the chance of two AR carriers having an affected child?

Answer 17

1 in 4

Question 18

Where might an AR disease show a pseudo-dominant inheritance pattern?

Answer 18

In consanguinous families.

Question 19

What pattern do autosomal dominant disorders show as on a pedigree?

Answer 19

Vertical. Grandparent, parent, child affected.

Question 20

What’s the chance of an adult with an AD condition having an affected child?

Answer 20

1 in 2

Question 21

What can the genetic mechanism be behind autosomal dominant disorders?

Answer 21

hapolinsufficiency, or GOF, or dominant negative effects (The mutant protein affects the function of the wild type protein).

Question 22

What is penetrance of AD conditions?

Answer 22

That those carrying the mutation don’t always show the phenotype. This may be a set percentage, or may be age related.

Question 23

What is the concept of expressivity with AD conditions?

Answer 23

It’s the degree to which people with an AD condition experience differing levels of severity of that condition

Question 24

What pattern do X-linked disorders show on pedigrees?

Answer 24

Knights move patterns. Affected males with affected uncles

Question 25

With X linked conditions males are _____ and females are usually _____

Answer 25

males are affected, and females are usually carriers

Question 26

For X linked conditions Sons of a female character have a 1 in ____ chance of being affected and daughters have a 1 in ____ chance of being a carrier. For an affected male, their sons have a 1 in _____ chance of being affected and a 1 in _____ chance of being a carrier

Answer 26

1 in 2 1 in 2 1 in 1 1 in 1

Question 27

What pattern of inheritance do mitochondrial disorders show on a pedigree?

Answer 27

Vertical pattern

Question 28

What is heteroplasmy in relation to mitochondrial disorders?

Answer 28

How there will be an extremely variable phenotype based on the proportion of affected mitochondria

Question 29

How are mitochondrial disorders passed on?

Answer 29

Through mothers

Question 30

The neurodegenerative disease Huntington's shows what feature of inheritance?

Answer 30

It's autosomal dominant. But has age related penetrance. And it shows anticipation.

Question 31

Freidrich's ataxia has what inheritance pattern?

Answer 31

Autosomal recessive

Question 32

If someone has a sibling with Friedrich's ataxia, an early onset disorder, what's the chance of that person being a carrier?

Answer 32

2/3 chance. Because we've ruled out them being affected, so there's only 3 options left.

Question 33

A man has a sibling with cystic fibrosis. What calculation do you need to do to work out the chance of him having an affected child?

Answer 33

His chance of being a carrier (2/3) * Chance of mum being a carrier from general population rate * 1/4 inheritance pattern

Question 34

If X-linked haemophilia A is in a family, what might be done during a pregnancy?

Answer 34

An amniocentesis at 34 weeks to genotype the baby to inform how the delivery should go.

Question 35

What are the two Hardy Weinberg equations?

Answer 35

P+Q=1 P2+2PQ+Q2=1

Question 36

In Hardy Weinberg equations when working with rare disorders, P is nearly always equal to what?

Answer 36

1

Question 37

Hardy Weinberg tells you what?

Answer 37

The proportion of homozygotes (for each allele) and heterozygotes in the population

Question 38

What would hardy weinberg with 3 alleles be?

Answer 38

P+Q+R=1 P2+2PQ+Q2+2QR+R2+2PR =

Question 39

What are males and females in hardy weinberg with x linked disorders?

Answer 39

Males are P or Q. Females are P2, 2PQ, or Q2

Question 40

Why doesn't simple hardy weinberg work with consanguinity?

Answer 40

You'll over estimate the incidence in the population and thus over estimate carrier frequency

Question 41

What are the basics of Bayes theorem?

Answer 41

You combine risk information that you know from different sources, then modify the probability based on conditions. So you work out the Prior risk due to population risk or family history. THEN add additional information regarding the Conditional probablility (e.g. test results, penetrance, unaffected children/siblings)

Question 42

Prior risk X conditional likelihood = ?

Answer 42

Joint/Final risk

Question 43

A man has a parent with a dominant allele for a disease with incomplete penetrance of 90%. This man has no symptoms. So what's the risk of him being a carrier using Bayes?

Answer 43

Well he has a 1/2 chance of having the allele as his prior risk from his parent. Then if he doesn't have symptoms that means he's in the 1 in 10 people without symptoms. So the joint risk is 1/2*1/10 =1/20. But he could be aa with no symptoms, which would just be a 1 in 2 chance. So 1/20 and 1/2 are our two options. So the chance of him being Aa/Aa+aa = 0.05/(0.05+0.50) = 0.5/0.55 = 1 in 11 chance.