What are the chances?
by Adrienne Sexton, Genetic Counsellor, & A/Prof. Michael Fahey, Neurogeneticist (Neurogenetics clinic, Royal Melbourne Hospital)
What are the chances of finding a gene change (DNA mutation) for HSP?
If no genetic testing has occurred previously for that person or family, the chance of finding a genetic cause seems to be about 50% (Lynch et al. 2016; Kara et al. 2016; Kumar et al. 2013). But if common genes like SPAST or SPG11 are excluded, the chance of finding a genetic cause for HSP in a family with no previous testing drops to around 25-30% (Kumar et al. 2013; Lynch et al. 2016; Kara et al. 2016). Chances of finding a genetic cause may be lower in populations where less is known about which HSP genes are the most common.
Why are different percentages reported in different studies?
Most of the studies so far have not had large numbers of participants, and have used multi-gene panels or exome sequencing. Some of the reasons that different research articles quote different DNA mutation detection rates for HSP are due to differences in:
- which individuals with HSP were included (their symptoms, age that symptoms began, population/ethnicity they are from)
- whether people had already been screened for the most common gene or genes, eg. the SPAST gene
- whether people had a family history of HSP, making it more likely that a dominant genetic cause will be found
- whether the researchers are including DNA variants that might be a cause of HSP as well as those DNA mutations that are already proven to cause HSP, and
- how many HSP genes were analysed.
What is Next Generation Sequencing (NGS)?
For many years, testing of the more common HSP genes (spastin, REEP1 and atlastin) one gene at a time was available, and the test would look through the thousands of letters of DNA code in one of those genes, to identify a change. This same principle of looking through the letters of the DNA code can now be applied to many genes at once. This is a leap forward in genetic testing technology and is called Next Generation Sequencing (other names are panel testing, whole exome sequencing, and Massively Parallel Sequencing).
Some types of gene changes go undetected
Some types of gene changes still will not be detected by this form of testing, and it is very likely there are undiscovered genes for HSP that may be able to be tested for eventually.
The types of gene changes causing HSP that will currently be missed are:
- when part or all of the gene is missing (deletions)
- when part or all of the gene is duplicated
- when there are repeated letters of the DNA many times over (eg. CAGCAGCAGCAGCAG)
- when the gene change affects the regulation of the gene, rather than the parts that code for the gene product (protein).
What are the different tests using next-generation sequencing?
Next-generation sequencing can be used in a number of different ways:
- multi-gene panels, where some or all of the currently known HSP genes are tested. Many panels have included 15, 20, 30 genes – more than 40 genes are currently known, and more than 70 genetic types of HSP, although not all the genes for these have been found.
- whole exome sequencing, where all known genes are sequenced, but due to the huge volume of DNA data, only genes for HSP and related conditions would be analysed. To keep this in perspective, we each have more than twenty thousand genes, so it is currently not feasible for the lab scientists to analyse each and every letter of the DNA code for each person’s test. Sometimes a condition is caused by a change to a single letter of the DNA code, which is like looking for a needle in a haystack.
- whole genome sequencing, where all known genes are sequenced plus all the “junk DNA” (98% of our genome) which is still largely unknown. See A Guide to Your Genome . Usually only genes linked with HSP and neuromuscular conditions would be analysed (due to the time and complexity of the analysis process) but this can check some of the regulatory regions of genes as well as the parts coding for the gene product (protein).
This website gives some more info about how genetic testing is used, depending on your own situation:
Kara, Eleanna; Tucci, Arianna; Manzoni, Claudia; et al. (2016). Genetic and phenotypic characterization of complex hereditary spastic paraplegia BRAIN Volume: 139 Pages: 1904-1918 Part: 7
Kumar, Kishore R.; Blair, Nicholas F.; Vandebona, Himesha; et al. (2013) Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia JOURNAL OF NEUROLOGY Volume: 260 Issue: 10 Pages: 2516-2522
Lynch, David S.; Koutsis, Georgios; Tucci, Arianna; et al. (2016) Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing . EUROPEAN JOURNAL OF HUMAN GENETICS Volume: 24 Issue:6 Pages: 857-863