Jorde: Medical Genetics, 5th Edition

Chapter 1: Background and History

Multiple Choice

1. Achondroplasia has a high mutation rate. This is most likely the result of
a. Paternal age effect
b. Maternal age effect
c. Large gene size
d. Methylated CG dinucleotide
e. None of the above

Answer: d

Correct Feedback: This has been shown to be the cause of achondroplasia.

Incorrect Feedback: This has not been shown to be the cause of achondroplasia.

2. The effect of mutations in the SHOX gene would best be described as
a. Haploinsufficiency
b. Dominant negative
c. Autosomal recessive
d. Gain of function
e. X-linked recessive

Answer: a

Correct Feedback: The effect is best described as haploinsufficiency.

Incorrect Feedback: This does not explain the effects of mutations in the SHOX gene.

3. Which of the following mechanisms is known to cause Prader-Willi syndrome?
a. Chromosome duplication
b. Translocation
c. Uniparental disomy
d. Autosomal trisomy
e. Autosomal monosomy

Answer: c

Correct Feedback: Prader Willi syndrome is effected by genomic imprinting. Thus, a uniparental disomy could cause the disease. 

Incorrect Feedback: This would not cause Prader Willi syndrome.

4. Suppose you have established that a disease gene is closely linked to a marker whose location is known. Which of the following would not be useful in defining the disease gene's location?
a. Testing for unmethylated CG islands
b. Existence of a chromosome deletion in a patient
c. Existence of trisomy in a patient
d. DNA sequencing
e. Testing for cross-species conservation

Answer: c

Correct Feedback: This would not be useful in defining the disease gene's location.

Incorrect Feedback: This could help you find the disease gene's location.

5. Which of the following is least likely to be seen in a patient with Huntington disease?
a. Dementia
b. Affective disorder
c. New mutation
d. Delayed age of onset
e. Loss of motor control

Answer: c

Correct Feedback: This is rarely seen in Huntington disease. It has one of the lowest known mutation rates of all human disease genes, estimated at approximately 1 per 1 million (per locus per generation).

Incorrect Feedback: This is seen with Huntington disease.

6. Which of the following is not a characteristic of osteogenesis imperfecta?
a. Locus heterogeneity
b. Allelic heterogeneity
c. Pleiotropy
d. Imprinting
e. Dominant negative mutation effects

Answer: d

Correct Feedback: Imprinting is more common with Prader-Willi and Angelman syndromes.

Incorrect Feedback: This is a characteristic of osteogenesis imperfecta.

7. In which of the following diseases are dominant negative mutation effects seen?
a. Huntington disease
b. Cystic fibrosis
c. Retinoblastoma
d. Marfan syndrome
e. None of the above

Answer: d

Correct Feedback: Marfan syndrome shows dominant negative effects.

Incorrect Feedback: One of the above shows dominant negative effects.

8. Which of the following is not true of Fragile X syndrome?
a. It is associated with methylation
b. It can be diagnosed using a karyotype
c. It is caused by a trinucleotide repeat expansion
d. It displays nearly 100% penetrance
e. None of the above

Answer: d

Correct Feedback: Fragile X syndrome is an X-linked dominant condition with 80% penetrance in males and 30% penetrance in females.

Incorrect Feedback: This is true of Fragile X syndrome.

9. Which of the following diseases follow(s) a "2-hit model"?
a. Osteogenesis imperfecta
b. Adult polycystic kidney disease
c. Cystic fibrosis
d. Retinoblastoma
e. B and D

Answer: e

Correct Feedback: e. Retinoblastoma and Adult polycystic kidney disease both follow a 2-hit model.

Incorrect Feedback: a. Osteogenesis imperfecta does not follow a 2-hit model.b. This is true but is not the only true answer.c. Cystic fibrosis does not follow a 2-hit model.d. This is true but is not the only true answer.

10. The recurrence risk for trisomy 13 is increased by
a. Advanced paternal age
b. 13/15 translocation in one of the parents
c. Extensive methylation of chromosome 13
d. Advanced maternal age
e. B and D

Answer: e

Correct Feedback: e. Both advanced maternal age and a 13/15 translocation in one of the parents increases the recurrence risk for trisomy 13.

Incorrect Feedback: a. Paternal age is usually not a factor in nondisjunction.b. This is true but is not the only true answer.c. This does not increase the recurrence risk for trisomy 13.d. This is true but is not the only true answer.

11. Which of the following is not correct about the XIST gene
a. It is expressed only on the inactive X chromosome
b. It produces an RNA product (which coats the inactivated X chromosome) but no protein product
c. It is expressed during embryonic development
d. It is expressed at twice the level in females as in males
e. All of the above are true

Answer: d

Correct Feedback: d. The mRNA transcripts are not detected in normal males at all.

Incorrect Feedback: a. This is correct about the XIST gene which is responsible for X inactivation in normal females.b. This is correct about the XIST gene which is responsible for X inactivation in normal females.c. This is correct about the XIST gene which is responsible for X inactivation in normal females.e. one of the above is false.

Jorde: Medical Genetics, 5th Edition

Chapter 1: Background and History

Sample Problems & Essay Questions

Question 1: Your class, which has 100 individuals, has been typed for a locus that has three possible alleles, labeled 1, 2, and 3. The genotypes and their counts are:
1,1 10 
1,2 5 
1,3 15 
2,2 20 
2,3 20 
3,3 30 

Based on these genotype counts, which is the gene frequency of allele 1?
Answer:   20+5+15      =     40       =      0.2
                     200                 200 
Question 2: If an X-linked recessive disorder affects approximately 1/1,000,000 females (all homozygotes) in a population, what is the expected frequency of affected males in the population?
Answer: q= √(1/1,000,000) = 1/1,000 
Question 3: Two individuals who both have achondroplasia (autosomal dominant disorder) mate. What is the occurrence risk for this disorder in their offspring?
Answer: 0.75 
Question 4: Suppose that you have done a carrier test for PKU (autosomal recessive disorder) in a population, and you discover that the heterozygote carrier frequency is 1/500. Based on this information, what proportion of the population will be affected with PKU? (Note: your answer does not have to be exact.).
   
Answer: 2pq=1/500 2q=1/500 q=1/1000 q2=1/1,000,000

Question 5: A woman with an X-linked dominant disorder mates with a phenotypically normal male. On average, what proportion of this couple's daughters will be affected with the disorder?

Answer: 0.50  

Question 6: A woman who is a heterozygous carrier of an X-linked recessive disease gene mates with a phenotypically normal male. The disease gene has a penetrance of 80%. On average, what proportion of this couple's sons will be affected with the disorder?

Answer: 0.8 x 0.5 = 0.4    

Question 7: In the accompanying pedigree, a man is affected with tyrosinase-negative oculocutaneous albinism (autosomal recessive). Based on this information alone, what is the probability that his grandson (labeled A) and his great-granddaughter (labeled B) are both heterozygous carriers of the albinism gene?

Answer: 1/8  

Question 8: A woman has an autosomal dominant form of postaxial polydactyly. Assuming that you have not examined any other family members to determine whether they have postaxial polydactyly, what is the probability that her second cousin (labeled A in the pedigree) is also affected with this fully penetrant disorder?

Answer:  (1/2)^6 + (1/2)^6 = 1/32

Question 9: Discuss the concept of pleiotropy. Use at least two disease examples to illustrate the concept. (This answer should require no more than about five sentences.)

Answer: Pleiotropy describes a common situation in which a single gene defect produces multiple phenotypic problems. There are many pleiotropic genes, some examples of which are: 

Marfan syndrome: fibrillin mutation causing ocular, skeletal, and cardiovascular problems (especially mitral valve prolapse and dilation of ascending aorta). 

Cystic fibrosis: mutations in the CFTR gene reduce chloride ion transport across the apical surface of some epithelial cells. This leads to elevated sweat chloride, pancreatic insufficiency (in most cases), and production of thick mucus in the airway. 

Neurofibromatosis type 1: mutations in the NF1 gene (encoding neurofibromin) can cause Lisch nodules, neurofibromas, skeletal defects (e.g., pseudarthrosis, sphenoid wing dysplasia), malignancies, hypertension, cafe-au-lait spots. 

Osteogenesis imperfecta: Mutations in type 1 procollagen lead to brittle bones, hearing loss, blue sclerae (in some cases). 

(Down syndrome was also accepted as an answer, although Down syndrome is not a single-gene disorder.)
      
Question 10: Hereditary diseases often present with no previous family history of the disorder. Briefly describe three situations in which you would be most likely to observe a genetic disorder for which there is no previous family history of the disease phenotype (three brief sentences should be sufficient).

Answer: Some possibilities: 

Autosomal recessive diseases usually have no previous history (consanguinity may be present, but usually is not for relatively common autosomal recessive disorders). 

New mutation transmitted by one of the parents. 

Germline mosaicism in one of the parents. 

Most chromosome abnormalities (aneuploidies, translocations, deletions, duplications) have no previous family history. 

Reduced penetrance can produce no previous history, although the penetrance would have to be very low. 

Anticipation is a possibility, although all diseases in which anticipation has been observed are dominant and thus they usually do have a previous family history.
    
Question 11: Match the pedigree with the most likely mode of inheritance. Note that complicating factors, such as reduced penetrance, may be present. Assume that the gene frequency of the disorder in the general population is very low. These answers may be used more than once.

 
 a. autosomal dominant 
 b. autosomal recessive 
 c. X-linked recessive 
 d. X-linked dominant 
 e. mitochondrial 
   
Answer: d

Question 12:  Match the pedigree with the most likely mode of inheritance. Note that complicating factors, such as reduced penetrance, may be present. Assume that the gene frequency of the disorder in the general population is very low. These answers may be used more than once.

 a. autosomal dominant 
 b. autosomal recessive 
 c. X-linked recessive 
 d. X-linked dominant 
 e. mitochondrial 

Answer: a