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Author: Laurie Ann Demmer, M.D.

Problem Solving in Genetics

  1. A woman with red-green colorblindness (X-linked recessive) and a man with hemophilia (X-linked recessive) have a son. State at which stage (maternal/paternal; meiosis I/meiosis II) the non-disjunction event(s) might have occurred for each of the following outcomes:
    1. 47,XXY (Klinefelter) son has neither colorblindness nor hemophilia.
    2. 47,XXY (Klinefelter) son has colorblindness only.
    3. 46,XY son has hemophilia only.
  2. A woman (Wilma) and her paternal aunt (Betty) marry related men. Betty’s husband is the maternal uncle of Wilma’s husband. Each couple produces a child with galactosemia (autosomal recessive; incidence is 1/100,000).
    1. Draw the pedigree.
    2. If Wilma and her husband had sought genetic counseling before having had a child (knowing that Betty and her husband had an affected child), what risks would you have cited for having affected progeny?
  3. Mrs C goes to the doctor. She has a very high white blood cell count. A karyotype analysis of her bone marrow cells shows 46,XX,t(9;22)(q34;q11.2).
    1. Is this a balanced or unbalanced translocation?
    2. What chromosomes are involved?
    3. Are the breaks in the short arm or the long arm? Is this likely to be a constitutional change or an acquired change?
    4. How could you check?
    5. If it's an acquired change, does the translocation pose a risk to any children she may conceive after treatment?
    6. If it is a constitutional change, would you expect this patient to have birth defects and/or mental retardation?
    7. If constitutional, does the translocation pose a risk to future conceptions?
    8. What are the possible meiotic outcomes if it is a constitutional change?
  4. JF and her husband have a history of pregnancy loss. A karyotype analysis of tissue from a recent loss shows:
    Karyotype 1
    Karyotype 1
    1. How many chromosomes are present?
    2. Is this a normal or abnormal karyotype?
    3. What is wrong?
    4. Is this balanced or unbalanced?
    5. What test would you do next, and what might you expect to find?
      Karyotype 2
      Karyotype 2
    6. Is this normal or not? Which chromosomes are affected?
    7. Which chromosome arm? Is this balanced or unbalanced?
    8. Would you expect this patient to be normal appearing and functioning?
    9. What gametes might she produce?
    10. Which ones are most likely to result in normal looking children?
    11. What options should you discuss with this couple regarding future pregnancies?
  5. Amelia is a 4-year old girl who had severe hypotonia and feeding problems as an infant. At the age of 3 years she began to gain excessive weight and now her weight is >95th percentile for age while her height is <5th percentile. She began walking at age 3 and, now at age 4, is just starting to talk. Routine chromosome testing is unremarkable.
    1. What additional diagnostic testing would you order and why?
    2. If testing shows a submicroscopic deletion of chromosome 15q, which parent do you predict passed on the deleted chromosome?
    3. What would the recurrence risk be for Amelia’s future siblings?
    4. If testing does not show a deletion, but rather reveals that both chromosome 15s were identical (isodisomy), which parent passed on two chromosome 15s and which parent passed on none? At what point in meiosis did non-disjunction occur?
  6. Mrs. S., a 36-year old woman, comes to clinic with a family history of Huntington Disease (HD). Her mother is affected and is currently severely debilitated in a nursing home. Her maternal uncle died 5 years ago with HD. Mrs. S. has a history of depression and alcoholism, although she has been (mostly) sober for 1 year. She has two sons, aged 18 and 6 years. Her neurologic exam is completely normal. She wants to have a genetic test for HD.
    1. How is HD inherited? What is the chance that Mrs. S. will develop the disease?
    2. Will you test her? Why or why not?
      After extensive counseling as well as discussion with Mrs. S.’ therapist, she decided to defer testing.
      Six months later Mrs. S. calls to say that her toes have begun to twitch, and she now wants to be tested for HD.
    3. Will you test her now? Why or why not?
      You arrange for Mrs. S. to see a neurologist who agrees that she has choreiform movements and sends the genetic test for HD. Results show that Mrs. S. has one normal allele (18 repeats) and one expanded allele (45 repeats).
    4. What will you tell Mrs. S. about her test result and how will you tell her?
    5. Mrs. S. asks you if her two sons should be tested. What do you tell her?
      Two weeks after being notified of her test results, Mrs. S. calls to tell you that she is 6 weeks pregnant.
    6. What is the chance that her fetus has inherited the HD gene? What are the options available to Mrs. S. regarding pregnancy management?
  7. Mr. and Mrs. D were seen for genetic counseling prior to amniocentesis for advanced maternal age. Mrs. D. is a 42-year old G4 P1 SAb 2 who is currently 16½ weeks pregnant. Incidentally, Mr. and Mrs. D. report that their 2-year old daughter Sharon has a history of failure to thrive and recently underwent DNA testing for cystic fibrosis; results are pending. There is no family history of cystic fibrosis or consanguinity.
    The following week Sharon’s test result returned. She has two different CF mutations: delta F508 and 3849+10kb C-T.
    1. Does Sharon have CF? What are the parents’ genotypes?
    2. Is there a risk for CF in the present pregnancy? If so, what percent risk?
    3. Assume by amniocentesis it takes approximately 3 weeks to complete prenatal testing for cystic fibrosis. Why does it take so long? What options does this couple have if the fetus is found to have CF?
    4. Mr. D’s sister, Caroline, is currently 12 weeks pregnant. What is the chance that her fetus is affected with CF? (Assume that her partner has no family history of CF, and that the incidence of CF is 1:2500.)
    5. Caroline tests positive for the delta F508 mutation; and no CF mutations are found in her husband. Assume that the mutation panel for CF detects 90% of carriers and misses 10%. Now what is this couple’s risk for having an affected fetus? Would you offer them amniocentesis? Why or why not?