Gene Testing- Questions and Answers

What is a gene and what is a mutation?
A gene is a small region that can be located on the DNA. Genes are units of inheritance. Each contains a coding sequence that determines the protein the gene produces.
An error in the coding sequence of a particular gene results in the gene producing the wrong protein and the error is called a mutation.. HSP genes have been identified and gene tests are used to identify the mutation.
What’s new for people with HSP and those at risk?
Gene tests are now available in Australia for the first time.
At the initiation of and funding by HSPRF, the Northcott Neuroscience Lab of ANZAC Research Institute has developed gene tests for three major HSP genes (SPG4, SPG3A and SPG6). Mutations in one of these three genes cause about half the incidence of HSP. In total there are 11 genes for which diagnostic tests are available world wide out of 31 HSP genes that have been located.
What kinds of tests are there?
There are 2 types of tests-the first is about discovering the causal mutation and the second is about screening for the presence or absence of the discovered mutation.
**Tests for discovery/detection of a mutation
This is the first step in determining the cause of the disorder in a family. It is conducted via a blood sample of a single family representative with the disease. The test will detect the mutation and establish the aberrant coding sequence and type of mutation.
The clinical geneticist or neurologist will consider the patients’ condition and nominate the gene for which a test is to be  conducted based on the type of HSP the patient appears to have, family history and their knowledge of the prevalence of each gene  (SPG4 is the most prevalent—30% to 40% of all HSP).
If the gene test is found to be negative, (no mutation can be found), the doctor and patient will consider the diagnostic issue again and may nominate the next most likely gene and so on until the mutation is found. Often families share in meeting the costs of mutation detection because the information is of benefit to all sections of the family.
If the mutation is still not found from these tests, arrangements can be made via the testing laboratory for the sample to be sent to a research laboratory overseas that seeks mutations in rarer genes and. This additional testing would be of no cost to the patient but the test would have to be repeated in a recognized testing laboratory for it to become clinically recognized and a cost would be incurred at this time.
**Predictive testing / pre-symptomatic genetic testing/screening
This is the diagnosis for the rest of the family when a family gene has been detected (see above). It is a more routine test and costs much less than the detection test.
With the knowledge of the family mutation, family members who are showing no physical signs of HSP can have their DNA screened for the presence or absence of the family mutation. As onset can be any time from childhood to 70years, many will want to know what their future may hold. This test can prove the absence of an HSP gene mutation in individual members of a family and will remove younger peoples’ concern about having children. It is always conducted in association with genetic counselling to help deal with the ramifications of both good news and not so good news. This test requires a consent form signed by the patient, 2 separate blood samples taken on separate occasions and genetic counseling involvement.
My neurologist has already told me I have HSP. Why do I need more tests?
You would have had tests in the neurologist’s clinic (reflex, scans etc) that indicate you have HSP. The term HSP is representative of a number of conditions caused by a mutation in one of 30 different genes. Hence you have been advised of the disease group affecting you but not the gene.
The gene test is carried out to:-
  • confirm the clinical test- some forms of MS present just like HSP in early stages. Any doubts you may have some other ‘brain / legs disconnect’ disease is eliminated.
  • determine the cause- the gene with the fault and the type of mutation
  • benefit relatives at risk by establishing the basis for existing and future family members who will then be able to screen for the presence or absence of the family mutation.
When I know my mutation how is it going to help me?
You have this knowledge but it is also available (with your consent) to other family members who can consider, with the genetic counselor, whether to screen for the presence or absence of the mutation (undertake predictive testing).
They can screen and, if they test positive, they can make more informed life choices including preventing their offspring inheriting the mutation, preparing for the likelihood of onset with physiotherapy, housing and health insurance choices and many others.
If they test negative they have eliminated what may have been a deep seated worry for them selves and their current and future children and their children.
You can see that your decision can have much wider ramifications than just your medical case ie. present and, as yet, unborn relatives at risk.
How do I get started?
Clinical genetics services are listed on the Centre for Genetics website and can be found, with phone numbers and addresses, at . If you are not on the internet, phone your local public hospital and, if they do not have a genetics service (some call it genetics counseling service) they will tell you the closest hospital that does.
How can my partner and I prevent our children inheriting HSP?
This is a subject that you and your partner should discuss with a genetic counsellor. However the essentials are set out below.
If the family mutation is not known then the partner concerned should undergo the mutation detection/ discovery test.
If the family mutation is known and the partner has not been tested for the presence or absence of the family mutation then that should become the first step. A negative result is good news.
Once a mutation is known the couple should have discussions with a genetic counselor on the options. There are three options:-
** 1 Pre-natal testing
A pre-requisite is the evidence of one parent with an HSP mutation that has been detected, referral from an appropriate doctor and a consent form signed by the mother-to-be undertaking the test. Genetic counseling applies.
Pre-natal testing involves taking a sample of the placenta at 11or12 weeks’ gestation, for DNA extraction and testing for the presence or absence of the known mutation
If the test result is positive (mutation is present) then the couple would make the decision whether to terminate or not with genetic counseling and medical advice.
** 2 Pre-implantation genetic diagnosis (PGD)
This method provides for only mutation free embryos being implanted to the womb of the mother to be.
A pre-requisite is evidence of one parent with an HSP mutation that has been described, referral of an appropriate doctor and a consent form signed by both parents. Genetic counseling applies.
PGD involves an IVF clinic and assisted reproduction technology including stimulation of ovaries to enable the collection of a number of eggs which are fertilized in the laboratory with prospective male parent’s sperm. The IVF Clinic takes an embryo biopsy of 4 to 6 cells on day 5 after fertilization. Then gene tests are performed on each cell to identify embryos without the mutation present and which can be used for implantation.
For some families at risk of passing on a genetic disorder to their children, PGD offers a more acceptable alternative to starting a pregnancy and later terminating.
For couples with a moral or religious objection to pregnancy termination and who also are at risk of having a child with the genetic condition, this technique may provide the opportunity to have an unaffected child.
** 3 Proceed with neither of the above interventions
Relevant Gene Testing News
*Some actual positives have tested negative
During 2006 European scientific team discovered that about 15% of tests for mutations in SPG4 tested negative when they were actually positive. A particular type of mutation (duplication/deletion) was being missed in conventional testing methods.
ANZAC Research Institute became aware of the findings before they were published. The German scientist leading the team assisted ANZAC R I in establishing the process for duplication/deletion testing to ensure this type of mutation is not missed. The weakness does not occur in the new Australian tests.
An Australian HSPer, who tested negative to SPG4 in a conventional overseas tests in 2004, actually tested positive from a sample contributed to the ANZAC R I research programme in 2006.
*Therapy may not be too far away- for some
A new drug that is in Phase 2 (for efficacy and safety in humans) trials for Cystic Fibrosis and Duchene Muscular Dystrophy is being watched by HSP groups around the world. This drug (PTC124) works only on a particular type of mutation (‘non-sense’ mutations) and, while the research focus has been on those two diseases, the manufacturers see it as likely to have much wider application.
The drug blocks the mutation’s message in the DNA to stop the production of a protein that is needed. The drug is unusual in that it targets non-sense mutations regardless of the gene and disease involved.
The new gene tests will record the type of mutation found and each person tested will know whether or not they have a non-sense mutation.
*The new HSP gene testing service is due to commence in Nov.