Genetic testing can be defined as an analysis or test that confirms the presence or the absence of a genetic condition.
This does not necessarily involve the analysis of DNA as there are still many clearly genetic conditions where the gene has not yet been identified.
In the context of Malignant Hyperthermia the IVCT test could be considered to be just as much a genetic test as the analysis of the RYR1 gene.
Genetic testing is different to the traditional medical test in that not only will the result have potential ramifications for the current health of that individual but it may also have ramifications for the future health of that individual and the future health of their immediate relatives. (Juengst 1999; Halsted 1996) Depending on the test being performed results may leave the individual disadvantaged in terms of their ability to access health insurance or life insurance, employment opportunities and in some cultures may even affect marital opportunities (Burke et al 2001; Fisher 1996).
For this reason it is recommended that each individual accessing any form of genetic testing, and indeed each individual undergoing IVCT or RYR1 analysis should be fully informed of all the implications of each potential result and should be able to provide informed consent (Skene 2002; Grover 2003).
The process of imparting this information and discussing any questions the patient may have is known as Genetic Counselling. This discussion, with a clinician or genetic counsellor should include the following points of information (Am. Soc. Hum.Gen. 1975):
- Potential implications the result may have on their ability to obtain health/life insurance. (Light 1992; Harper 1993)
- Potential psychological effects of the result. Some parents feel guilty that they may have passed MH sensitivity on to their children, others may feel anxious about the implications of a MHS result and experience an increased fear of surgery, others may even feel guilty if they have not inherited MH when their brother or sister has. (Kessler et al 1984; Marteau et al 1998; Jacobs et al 1999)
- Inheritance pattern of the disorder and what implications their test result may have for their children, and the extended family.
- If there is also a family history of CCD, it is important that the potential diagnosis of this condition is not lost in the discussions regarding Malignant Hyperthermia. CCD is an extremely variable condition within families and while some individuals may only be very mildly affected other family members may have a more severe phenotype (Quinlivan et al 2003).
Interpreting Risk for Other Family Members.
Malignant Hyperthermia is an autosomal dominant condition. When initiating genetic analysis in a branch of a known family it is important to test the individual at the highest risk first.
- Parents of a proband: the large majority of times an affected proband will have inherited their MH sensitivity from one of their parents. Clarification of which parent may also be MHS is useful for identifying which side of the extended family (ie aunts & uncles) may be at risk.
- Siblings of a proband: The risk to the siblings depends of the genetic status of the parents. If a parent is identified as MHS, then each of the proband’s siblings have a 1 in 2 or 50% chance of also being MHS. (If both parents receive an MHN result on IVCT & RYR1 analysis – suggesting the mutation is de Novo in the proband - then the proband’s siblings are at no greater risk than the general population.)
- Offspring of a proband: The risk for offspring of each individual with proven MHS also has a 50% chance of being MHS. The proband’s grandchildren would be considered to be at 25% risk until their parent’s genetic status is clarified.
- Note: An individual who is MHN cannot pass MH Sensitivity on to the next generation, however, if they have an affected parent their siblings may still be at risk.
Interpretation of Risk for Other Family Members in the Context of RYR1 Analysis.
As discussed in earlier sections the identification of a causative RYR1 mutation is sufficient to diagnose MH Sensitivity. However, due to current concerns regarding discordance between IVCT and mutation analysis in some families, current protocols state that a negative mutation result is not sufficient to identify a person as being MHN. In the event of a normal (negative) mutation result IVCT is still recommended to confirm MHN status, and the individual and his/her offspring are still considered to be potentially MHS unless IVCT proves otherwise (Robinson et al 2003).
However, it is important to remember that in the event of a normal (negative) mutation result – the offspring of the individual are no longer at risk of inheriting the characterised family mutation. As the tested individual does not carry the mutation he cannot pass it on to his offspring. Therefore, if an individual is mutation negative but IVCT positive, the only useful test available to the offspring is IVCT.
Final note on Autonomy in Clinical testing for Malignant Hyperthermia.
Some individuals may wish to delay IVCT or RYR1 analysis while they consider the information they have been given and/or make the necessary preparations. Others may decide that they do not want their risk clarified by clinical testing.
These decisions should be respected and these individuals considered to be MHS until proven otherwise.
Care should then be taken when arranging testing for the offspring of these individuals as a positive result in the next generation will generate a result for the individual who did not want to know (the individual must have carried the gene mutation in order to pass it on).
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Ms Danielle James BSc(Genetics);Grad Dip Genet Counsell; FHGSA(Genetic Counselling)
Central & Southern Regional Genetic Services,
Private Bag 7902,