Genetic Counseling

Genetic counseling encompasses the clinical, technical and psychosocial components of genetic testing and disease. The genetic counseling process is both an opportunity for patients to explore their questions and concerns about genetic disease and testing as well as a means for medical professionals to develop comprehensive clinical histories and gain an understanding of the unique needs of their patients.

The following components may be part of a genetic counseling session:

• Development of detailed personal and familial medical histories
• Discussion of testing options and capability
• Assessment of genetic risk to patient and family members (may include Bayesian analysis)*
• Psychosocial discussion and support
• Reproductive decision making / Prenatal diagnosis options
• Discussion of test results

*Bayesian analysis is a mathematical method used to calculate recurrence risks of genetic diseases. The method synthesizes information from different sources (genetics, pedigree information, and test results) to calculate the probability that an individual might transmit or develop a genetic disorder.

Case Study Examples

Case Study #1: Myotonic Dystrophy

A 28-year-old woman, Molly, informs her doctor during a first trimester prenatal visit that she is affected with Myotonic Dystrophy (DM). Previous molecular testing indicates that Molly has an expansion of 140 trinucleotide repeats in one of her DMPK genes. She states that the disease had not had a major impact in her life and her symptoms have not been severe. Given that her father also has mild symptoms, Molly feels that if her baby happens to inherit the mutation, the baby will also have a similar course of symptoms.

Molly's concept of DM is perfectly understandable; why wouldn't a genetic disease have a consistent clinical picture among family members? The symptoms may not be the same, explains her doctor, because of anticipation. Anticipation refers to the phenomenon of increased severity and earlier onset of genetic disease when a mutation is transmitted from one generation to the next. The mechanism of anticipation is an increase in the number of trinucleotide repeats during the production of gametes. In the case of DM, anticipation is influenced by the gender of the affected parent. If the affected parent is female, there is a risk of significantly increased expansion in offspring such that a mildly affected woman may have a child with classical or congenital DM.

Following a discussion about prenatal diagnosis, Molly decides to have an amniocentesis to determine if her fetus inherited her expansion. She tells her doctor, "If my baby inherited the expansion, at least you can tell me if he will be mildly or severely affected." Again, the situation is not so clear. Molly's doctor explains that clinical severity cannot be unequivocally determined from the number of trinucleotide repeats. An individual with Molly's own number of repeats, 140, may be only mildly affected or may have classical symptoms. However, the prenatal finding of an expansion of greater than 1,000 repeats would indicate that her baby would likely be severely affected.

Case Study #2: Duchenne Muscular Dystrophy (DMD)

Andy is a 3 year-old boy who was very active according to his mother until the last couple of months when he has begun to have difficulty with normal activities such as climbing the stairs and getting out of his toddler-sized chair. Recognizing classic-presenting signs of DMD, Andy's doctor decides to test his patient's serum creatine kinase (CPK) levels. Upon finding that Andy's CPK levels are 100 times greater than the normal range, the doctor feels strongly that his patient probably has DMD.

When the doctor raises this possibility with Andy's mother, she replies that no one in their family has DMD so she doesn't understand how her son could have it. Andy's doctor explains that while two-thirds of cases are familial, about a third of DMD cases are de novo, or sporadic, meaning that the mutation arose spontaneously and is not possessed by other family members. Therefore, a negative family history does not rule out the possibility of DMD.

Andy's mother feels a great deal of relief when the molecular testing results for Andy are negative for a deletion in the dystrophin gene. Unfortunately, this result still does not rule out the diagnosis. Andy's doctor explains that 60 to 65% of patients with DMD will have a deletion, however, a 30 to 35% of cases are expected to have some other type of mutation including a duplication or rearrangement. In order to establish a definitive diagnosis, the doctor decides to perform a muscle biopsy for a dystrophin protein analysis. The result of this analysis confirms the diagnosis of DMD; Andy has less than 5% of the normal levels of dystrophin protein.

"Are my other children at risk?" Andy's mother asks in a subsequent visit. To answer this question, Andy's doctor describes three possible scenarios. Without performing any tests on Andy's mother, there is about a two-thirds chance that Andy's mother is a carrier. If she is indeed a carrier, Andy's brothers are at a 50% risk of being affected with DMD and his sisters are at a 50% risk of being carriers. Linkage analysis may be informative in predicting carrier status for Andy's sisters. Second, Andy may have a de novo mutation. If Andy's mutation is de novo, his mother is not a carrier and his siblings are not at risk for inheriting the mutation. Third, Andy's mother may have germline mosaicism (presence of mutated as well as normal alleles in the cells which produce gametes) for a DMD mutation. Given that Andy is the only member of his family to be diagnosed with DMD, it is not possible to rule out the 15% possibility of germline mosaicism in Andy's mother. If Andy's mother is germline mosaic, her children are at risk for inheriting a mutation.