HNPP · Physical Health

Why do some HNPP results appear negative?

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Genetic testing for HNPP can be daunting, mostly because it can be a confirmation of all your worst fears. At the same time, it can come as a relief for many, as it marks the start of an official journey. But what happens when your results turn up negative?

As the NHS website explains, we need two peripheral myelin protein-22 (PMP22) genes, one from each parent, for the normal development of the peripheral nerves. These genes provide instructions for the creation of PMP22 protein, which makes up the protective outer layer of each nerve. This outer layer, which is a bit like the plastic coating that insulates a wire, is called myelin.

“It would have been nice to feel the immediate gratification of a positive HNPP test result. It would have answered nearly every question I had about what was happening to my body.”

From the Girl With A Purple Cane blog

In HNPP, one copy of the PMP22 gene is lost (deleted) so that people have only one copy of this gene. A person with HNPP will have inherited a faulty copy of the PMP22 gene from one of their parents.

With only one normal PMP22 gene, their myelin is fragile and more susceptible to injury. Just the slightest pressure, stretch or repetitive movement on the nerve causes sections of the myelin to be lost. Signals cannot be relayed to and from the muscles properly.

A genetic test usually confirms whether one of the copies is deleted. Around 80 per cent  of cases of HNPP is down to deletions of this particular gene. However, in some cases even with a genetic test, it can come back negative.

According to DNA diagnostic experts GeneDx, genetic diagnosis is identified in approximately 50-70 per cent of individuals with the hereditary neuropathic condition Charcot-Marie-Tooth disease, which shows that even if the symptoms present themselves, they may not be explicitly diagnosed for all.

This was seen in a 2006 study where a 32-year-old woman diagnosed with CMT, where the PMP22 genes are duplicated, came back with a false negative even though she had two different types of gene mutations.

gene testing HNPP hereditary neuropathy
Algorithm for Peripheral Neuropathy testing – GeneDx

What happens if the results are positive?

A positive result indicates that a disease-causing mutation was identified in the individual who was tested. In this case, you can get predictive genetic testing in terms of planning ahead as well as testing for your family. They can then go ahead for further evaluation. There can be variability in symptoms, age of onset, and disease severity even among members of the same family who have the same genetic mutation.

What if the results are negative?

Even with a negative test result, it does not rule out that a person with neuropathy does not have a genetic condition. As the diagnostic company suggests possible reasons for a negative result could be:

  • The patient has a mutation in a gene not included in the testing panel
  • The patient may have a mutation in a part of a neuropathy gene that was not covered by the test
  • The patient does not have hereditary type of neuropathy

As Sharon Plon, Medical Geneticist and Director of MD-PhD program at Baylor College of Medicine, says:

Unknown results

In some cases, results may not conclusive either way. These results are referred to as variant of unknown clinical significance (VUS). This indicates that the role of the genetic change in causing neuropathies has not clearly been established. In some cases, testing of other family members may help clarify the clinical significance of a VUS.  The greater the number of affected family members who carry the VUS, the greater the likelihood that the identified variant is hereditary.

In other instances, if the person is the only one identified with a single mutation, they may be a heterozygous carrier i.e. they inherit a pair of genes where one is dominant and one is recessive.

Advantages of getting a panel test if negative

  • Higher diagnostic rate
    • all ‘common’ genes in one test
    • the rare genes included/ genes that no diagnostic service is available
    • more patients and families to get a genetic diagnosis
  • Faster turn around time
    • all genes in one test, not sequential testing
  • Familial cases can avoid further clinical investigations
  • Enhance our knowledge and understanding for IPN genes (Enrich for fragments of interest)
    • routine testing of rare genes
    • interaction between genes/ modifying mutations
  • Cost savings
    • directly: panel testing is cost effective
    • indirectly: faster result / high diagnostic rate can lead to reduced
    • appointments and other investigations for patient and family

However, the cost of a genetic test depends on the complexity of the test and can range from under £100 to £1000s, for example a basic chromosome test (karyotype) would cost about £150 and screening a panel of 108 genes associated with congenital cateracts costs £1100. The cost increases if more than one test is necessary or if multiple family members need to be tested. So it can be a hefty investment depending on where you’re getting it done.

The problems with certain gene tests

Either way, as some research states, the CMT1A duplication was identified more frequently than the HNPP deletion, suggesting some types of gene variants are more difficult to detect to than others such as those for HNPP.

The study, Charcot-Marie-Tooth Disease And Related Hereditary Polyneuropathies featured in the Genetics in Medicine journal, says: “HNPP can mimic multifocal neuropathy, a frequently inflammatory disorder that requires immunosuppressant therapy.

“Molecular testing occasionally identifies new sequence variations of unknown pathogenic significance. In these cases further studies (segregation analysis, functional assay) are required to establish pathogenicity, which are performed in research laboratories.”

Hence there is still quite a lot of testing to be done to perfect the current sequencing method. So hopefully it won’t come as a shock if your results turn out to be negative, but be prepared for that eventuality.

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