Depending on where a person is diagnosed, and the type of health care that they receive, genetic testing for HNPP can be highly variable. Not all labs do all possible tests for the known mutations that cause the HNPP phenotype.
The following link is to the Molgen Database for Inherited Peripheral Neuropathies, by selecting look up mutations by phenotype the following table is displayed for HNPP,
(awaiting permission to reproduce table of mutations from Molgen database)
Most of these mutations involve the PMP22 gene, No.2 is the most common 1.5megabase pair deletion found on chr 17p11.2. This is the most commonly tested mutation, and depending on the tests requested, location, and type of healthcare, maybe the only test available.
When my son and I were diagnosed, I was tested for the common deletion only, this was in 2001. Because I have no previous family history and it was suggested that I could be a new mutation, I asked whether I had one of the rarer mutations of pmp22 rather than the common deletion. I was told quite unequivocably that had that been the case I would have tested negative, as they did not have the fascillities to test for the rarer mutations.
Before the molecular genetics of HNPP were understood, everyone who was diagnosed with HNPP was done solely by clinical testing, exclusion of other forms of peripheral neuropathy, CT scans and latterly MRI scans, examination of CSF (spinal tap), nerve conduction studies to determine the type of neuropathy ie demyelinating or axonal, a sural nerve biopsy, and noting any familial traits. Often the biopsy would be the clinching evidence for HNPP or rather Tomaculous neuropathy as it was often known at the time.
Today biopsies are less favoured, although it is likely that someone with neuropathy would have had a multitude of exclusion tests, nerve conduction studies and clinical testing before the request for the DNA screening is submitted.
While it is becoming increasingly rare it is absolutely possible for someone to be diagnosed with HNPP by exhaustive clinical testing and yet have a negative genetic test. A negative test can mean that no test is currently available in that region, for that person’s genetic marker.
This of course still leaves the person in limbo to some extent, with questions to ask, and due to the negative test many anxieties. Further testing may be neccessary to continually exclude other possible causes. It is not a particularly satisfactory outcome for the patient. In some ways one could say that the diagnosis of HNPP is provisional, but stands until further testing can definitively find the cause of the neuropathy.
On Maureen Horton’s HNPP.org website, it was estimated that upto 20% of those diagnosed with HNPP by clinical testing had a negative genetic test. Whether that statistic still stands today is debatable, considering the advancements of genetic testing and the number of HNPP mutations discovered since that time. But there will always be a few cases where all due diligence indicates HNPP and yet genetic tests are negative, at least until whole genome sequencing is available, but that appears to be someway off in the future.
Finally, the case with CMT is even greater, there are far more types of CMT, some are well known like CMT1a, but there are many rarer types, indeed there are a few unique types that are mutations which are only found within one family pedigree. The genetic basis of these, required immense effort and resources to instigate a unique genetic study. This type of testing is just not available for most people who have a type without a known genetic marker. No one would dispute that someone didn’t have CMT because they don’t have a positive test, such diagnoses carried out by clinical testing alone, are far more common in CMT than HNPP, and they are well accepted. The same should be true of the fewer numbers with an HNPP diagnosis by clinical testing who also do not currently have a known genetic marker.