Fragile X syndrome

Case ACase BCase C
Contributed by Gretchen Hessler, Melissa LeFebvre, and Jenni Swanson, University of Wisconsin – River Falls

Background:  Fragile X syndrome is the leading cause of inherited mental retardation.  The mutated gene that causes the disorder is called fmr1 and is located on the long arm of the X-chromosome.  It is currently unclear whether this trait is dominant or recessive, because both types of expression have been demonstrated.

The mutation involves exaggerated repetition of the CGG triplet in a portion of the fmr1 gene near the 5′ end.  Those with a functional gene have 6 to 50 CGG repeats, whereas those with a full mutation have 200 or more such repeats.  Between 50 and 200 repeats of the codon constitute a premutation.  An individual with a premutation is considered a carrier, but does not display any symptoms of fragile X.  A premutation may undergo additional repetition to generate a full mutation.

DNA testing began after the fmr1 gene was discovered in 1991. Prior to this discovery, those with this disorder were often diagnosed as being learning disabled, autistic, or hyperactive.  With the advent of DNA testing, accuracy of diagnosis has increased tremendously.

Procedure: To analyze these cases, digest each of the DNA samples with EcoR1.  Then perform a Southern blot using the probe corresponding to the region of the fmr1  mutation to determine the genotype of each individual.

Case A:   Doug and Grace are expecting their third child.  They have recently learned of fragile X syndrome and strongly suspect that their son, Brad, might have this disorder.  For this reason, they would like their family to undergo genetic testing.  Their daughter, Katie, shows no symptoms of fragile X.  They also decide at this time to test the fetus for the same disorder.

DNA samples:

  • Doug
  • Grace
  • Brad
  • Katie
  • Fetus
  • Control normal DNA
  • Control DNA with premutation
  • Control DNA with full mutation
  1. What conclusions can you draw from the gel results?
  2. What options are available to the parents?
  3. What issues are raised by this type of testing?

Case B:  Melissa has always found dealing with her brother, David, very difficult.  His developmental disability and behavior problems were an embarrassment to her as she was growing up.  When she married Paul and moved away, she was delighted finally to be free of her “problem brother.”  However, her freedom for her “problem” is to be very short lived.   She and Paul want to start their family as soon as possible and Melissa gets pregnant soon after their marriage.  When Melissa calls home to tell her family the good news, her mother, Emma, bursts into tears.  Melissa listens in shock as her mother tells her that their family physician has learned of new research on a genetic condition called Fragile X Syndrome and has suggested that this might be the cause of David’s problems.  Emma and David have already made an appointment for genetic testing and Melissa quickly decides that she and her fetus should also be tested.

DNA samples:

  • David
  • Emma
  • Melissa
  • Fetus
  • Control DNA with premutation
  • Control DNA with full mutation
  1. What is the chance that Melissa is a carrier?
  2. What conclusions can you draw from the results of the DNA analysis?
  3. How would you counsel Melissa based on the results of her test?
  4. What issues may be raised by the results of the testing?

Case C:  As Janet, Beth and Alison sit in the reception area of the genetics clinic, they discuss their anxiety about the upcoming test results and their anger at their mother.  Ever since Uncle Al, their mother’s brother, was diagnosed with Fragile X Syndrome, their family has discussed genetic testing for the disorder.  Their mother has steadfastly refused to consider being tested and even her unexpected pregnancy at age 42 has had no effect on her decision.  The daughters have decided that they will be tested because they want to know their status and also because they intend to use any positive results as leverage to convince their mother to change her mind about testing for her and the fetus.

DNA samples:

  • Janet
  • Beth
  • Alison
  • Control normal DNA
  • Control DNA with premutation
  • Control DNA with full mutation
  1. What conclusions can you draw from the results of the DNA analysis?
  2. How would you counsel Janet, Beth and Alison based on the results of their tests?
  3. What issues may be raised by the results of the testing?
  4. Does their mother have a right not to know the results?
  5. What other genetic counseling issues are there for their mother?