Bayes Tutorial 2022 (7 pages)

BGEN 3022 - Pedigrees

Instructions: Complete all questions prior to class on December 6th. Come prepared to review the
answers together in class to practice Bayes calculations prior to the final exam.

1. Vivienne (woman) had a brother who died from X-linked severe combined
immunodeficiency (SCID). Vivienne has a son and a daughter. The son also had SCID.
The daughter had 2 healthy sons and a healthy daughter (Nora). Nora is now pregnant
with a male fetus. Assuming DNA testing is not available, what is the chance that Nora’s
fetus will have SCID?

Nora’s mom Carrier Non-Carrier

Prior 1/2 1/2
Condition (1/2)2 = 1/4 4/4
Joint 1/8 4/8
Posterior 1/5 4/5

Risk for fetus = 1/5 x ½ x ½ = 1/20

2. An Ashkenazi Jewish (AJ) couple had been seen in your clinic for preconception
counselling. Carrier testing has revealed that the woman is carrier of Familial
Dysautonomia. Her partner had negative carrier testing for Familial Dysautonomia
(testing for common AJ mutations: sensitivity 99%). Calculate the risk for this couple to
have an affected child given that the carrier frequency of this disorder in the AJ
population is 1/30.

Couple Partner Carrier Not Carrier

Prior 1/30 1 – 1/30 = 29/30
Condition (neg carrier test) 1/100 100/100
Joint 1/3000 2900/3000
Posterior 1/2901 2900/2901

Risk for affected child: P(carrier) x P(partner carrier) x P (both transmits allele)
1 x 1/2901 x ¼ = 1/11604
3. Max is a healthy 40-year-old man whose father is in a care home with end-stage
Huntington disease (HD) that was confirmed on molecular analysis (he was
heterozygous). Max has no significant previous medical history apart from being a drug
user for 10 years from ages 25-35 which he says was the result of a long-standing
abusive relationship with his father. Max has not spoken to his father for over 15 years
and has an on-off relationship with his mother, but he is in touch with his sister. She had
a normal HD predictive test a few years ago and currently helps to look after the family
affairs.

Max’s clinical exam was normal. Assuming that 30% of individuals heterozygous for the
HD gene show symptoms by age 40, what is Max’s risk of being heterozygous for the HD
gene?

Max Carrier (heterozygous) Non-Carrier (not heterozygous)

Prior 1/2 1/2
Condition (healthy @ 40) 7/10 10/10
Joint 7/20 10/20
Posterior 7/17 10/17
4. Draw the following pedigree:
Adam and his wife Janice had a daughter Daphne and 2 sons Ralph and Saul. Daphne
and her husband Isaac had a daughter Leah and 4 sons Noah, Sebastien, Jacob and
David. Ralph and his wife Susan had a daughter Rachel who married Daphne's son
David. Jacob and his wife Ruth had a son Sampson. Leah is married to Erik. Sampson is
married to Leah and Erik’s daughter, Delilah. Sebastien has cystic fibrosis (CF) which is
an autosomal recessive disease with a 1/25 carrier frequency. Noah and Saul both died
of complications of Duchenne muscular dystrophy (DMD) which is an X-linked recessive
lethal disorder.

a. If Daphne had a normal CK what is the chance she is a carrier for DMD? (2/3 of
carriers for DMD have an elevated CK)
Answer: 100% - must be an obligate carrier

b. If Leah had 2 healthy sons and a normal CK and is pregnant with her 3rd son,
what is the chance that the child will have DMD?
Leah Carrier Non-Carrier
Prior 1/2 1/2
2
Condition (2 N sons) (1/2) = 1/4 4/4
Condition (N CK) 1/3 3/3
Joint 1/24 12/24
Posterior 1/13 12/13
c. What is the chance that David and Rachel will have a child with CF?
2/3 x ¼ x ¼ = 1/24

d. What is the chance that Sampson and Delilah will have a child with CF?
1/3 x 1/3 x ¼ = 1/36
5. Marsha’s syndrome is an autosomal dominant late onset neurological condition. By 35
years of age, 40% of individuals are affected. By 70 years of age, 90% of individuals are
affected. A man’s paternal aunt and grandmother are both affected. If a man’s paternal
aunt and grandmother are both affected, what is chance for him to be heterozygous for the
disease allele? The man is 35 and his father is 71 and neither have any symptoms.

Father Carrier Non-Carrier

Prior 1/2 1/2
Condition (N @ 70) 1/10 10/10
Joint 1/20 10/20
Posterior 1/11 10/11

Son Carrier Non-Carrier

Prior 1/22 21/22
Condition (N @ 35) 6/10 10/10
Joint 6/220 210/220
Posterior 6/216 = 1/36 210/216

6. About 1 in 10 individuals who are African-American are carriers for sickle cell anemia. A
woman who has one child with sickle cell anemia and one unaffected child, both with her
first husband, marries a second time to a different man who is also African-American. If the
result of her second husband’s sickle cell screening is unknown, and they already have one
unaffected child, what is the probability that their second child together will have sickle cell
anemia?

Couple Both Carrier Both Non-Carrier

Prior 1 x 1/10 = 1/10 9/10
Condition (1 N child) 3/4 4/4
Joint 3/40 36/40
Posterior 3/39 = 1/13 36/39
Next child to be affected: 1/13 x ¼ = 1/52
 7. A couple has 2 sons (Scott and Ed) affected with Kennedy disease and one unaffected
daughter (Claire). Kennedy disease is inherited in an X-linked recessive manner.
a. What is Claire’s risk to be a carrier of Kennedy disease?
Answer: ½

b. What would be Claire’s risk to be a carrier if she already had 3 unaffected sons (Jon,
Stephen and Tyler)?

Claire Carrier Non-Carrier

Prior 1/2 1/2
Condition (1 N child) (1/2)3 = 1/8 8/8
Joint 1/16 8/16
Posterior 1/9 8/9

c. Tyler and his wife are considering a pregnancy. What is their risk to have an affected
child? (the wife has no family history of Kennedy disease)
Answer: low (new mutation rate)

d. Claire also has an unaffected daughter (Kay) who has a daughter of her own
(Jessica). What would Jessica’s risk be to have a child affected with Kennedy disease?
Answer: 1/36 x ½ x ½ = 1/144

8. Noelle and Jason are expecting their first child in a few months. Noelle’s sister Jenny
recently had a baby diagnosed through newborn screening with MCAD deficiency
(homozygous for the common mutation in ACADM c.985A>G). Noelle and Jason had their
DNA tested for the common mutation above which detects 40% of carriers. Noelle’s carrier
test failed and did not provide a result. Jason was shown not to be a carrier for the common
mutation. MCAD carrier frequency is 1:40. What is the risk for their unborn baby to be
affected with MCAD?

Jason Carrier Non-Carrier

Prior 1/40 39/40
Condition (1 N child) 6/10 10/10 = 1
Joint 6/400 390/400
Posterior 6/ 396 = 1/66 390 / 396
Risk
for pregnancy: 1/66 x ½ x ¼ = 1/528
9. Ira (man) and Elizabeth (woman) are a couple, each have a sibling affected with PKU
(autosomal recessive).
 a. What is the prior risk that they are both carriers?
Answer: 2/3 x 2/3 = 4/9

b. What is their risk of having an affected child?

Answer: 4/9 x ¼ = 1/9

c. If they have 3 unaffected children, what is the risk for their next child to be affected?

Couple Both Carrier Both Non-Carrier

Prior 4/9 5/9
Condition (3 N children) (3/4)3 = 27/64 64/64
Joint 108/576 320/576
Posterior 108/428 320/428

10. A 30 year old woman with a clinical diagnosis of myotonic dystrophy is seen for counselling.
Her son is 14 years old and wishes to know if he will be affected. He is currently
asymptomatic. The lifetime penetrance of this condition is very high, but the age of onset
varies; approximately half of all individuals carrying the gene will remain asymptomatic at
age 14. What is the risk that the son will eventually be symptomatic assuming he lives past
age 50?

Son Carrier Non-Carrier

Prior 1/2 1/2
Condition (N @ 14) 5/10 = 1/2 10 /10 = 1
Joint 5/20 = 1/4 10/20 = 1/2
Posterior 1/3 2/3
 11. In the following pedigree, patient 1 has an autosomal dominant disorder. Population
studies show that this disease is 40% penetrant.

a) What is the chance that patient 6 carries the mutant gene?

#3 Carrier Non-Carrier
b) #6
Prior Carrier
1/2 Non-Carrier
1/2
Prior
Condition (2 healthy sons) 3/16
6/10 13/16
10/10
Condition
Joint (2 healthy sons) 6/10
6/20 10/10
10/ 20 = ½
Joint
Posterior 18/160
6/16 130/ 160
10/ 16
Posterior 18/148 = 9/74 130/ 148
What is the chance that patient 6’s fetus is affected?
Answer: 9/74 x ½ x 4/10 = 9/370
12. A man with hemophilia A (X-linked recessive) has an unidentified mutation in the F8 gene.
He has two unaffected children, Tracy (daughter) and Patrick (son). Tracy has two
unaffected sons and a daughter, Jill. Jill has four unaffected sons and is pregnant again.
What is the risk for Jill’s current pregnancy to be affected with hemophilia A?

Jill Carrier Non-Carrier

Prior 1/2 1/2
Condition (2 healthy sons) (1/2)4 = 1/16 16 /16 = 1
Joint 1/32 = 16/ 32 = 1/2
Posterior 1/17 16/ 17
Risk to pregnancy: 1/17 x ½ x ½ = 1/68