Written by Mary Kelley, DO
University of Texas Dell Seton Medical Center
Some forms of small-fiber neuropathy (SFN) stem from mutations in genes necessary for proper form or function of peripheral nerves. These mutations are most often passed from parent to child, and are called inherited or genetic neuropathies. Some mutations affect proteins in the nerve cell membrane, leading to chemical changes in the cells that result in neuropathic pain. Other genetic defects cause the nerves to be overexcitable, so that the person feels pain despite lack of injury. In most cases of inherited neuropathy, symptoms start in childhood. Genetic testing may be appropriate for some patients if their symptoms or test results suggest they may have an inherited/genetic basis for their neuropathy.
Who should get genetic testing for SFN?
People who have been diagnosed with small-fiber neuropathy of unknown cause (“idiopathic SFN”) should first be screened for possible genetic disease using parent and family histories and prior test results. Genetic testing may be considered in adult patients with idiopathic SFN, and is indicated in all children who have idiopathic SFN, even if they don’t have a family history. More intensive testing, including genetic sequencing can be particularly beneficial in pediatric patients, people with a family history of SFN, and individuals with highly specific presentations of the disease.
What genetic test is best?
Genetic testing often involves the analysis of a select set of genetic mutations already known for their involvement in SFN, and whose identification can give your neurologist actionable information to steer your treatment. As we come to know more about the genes involved in SFN, those panels may be further expanded or narrowed. Other tests could involve analyzing the full genetic code of single or multiple genes, or the entire genome. These tests have the potential to identify new disease-causing mutations or genes, but are more expensive than existing standard genetic screens. The choice of genetic test is often driven by cost, and as genetic sequencing becomes more affordable, the relative values of sequencing single genes or gene panels versus the whole genome changes.
The results of genetic tests are not final. As our understanding of the genome and its variation evolves, so, too, will the tests themselves, and the meaning of the results. At best, the results will reflect what is known about genetic variants and SFN at the time of the test. Results that are unrevealing initially may later be found to be informative.
Ultimately, it is important to talk to your neurologist about whether genetic testing would be appropriate for you. Together, the two of you can decide if the possible benefits outweigh the cost of the testing.
Taking a closer look at genetic testing
Genetic testing provides information on your genetic makeup, or genotype, to determine if there are genetic factors that may be contributing to your disease. First, it is important to understand the difference between the genotype and the phenotype of a person.
A person’s genotype is his or her genetic constitution. It refers purely to the composition of the DNA and contributes to, but does not alone dictate, physical characteristics.
A person’s phenotype is the set of observed characteristics he or she displays at any given point in time, and it results from the interaction of genotype with their environment.
In people with neuropathy, a genotype can provide information for diagnostic purposes. However, in many cases, having the genotype associated with a particular disease does not guarantee that a person will have that disease. In fact, many of us likely carry genetic variants that are associated with diseases we will never develop.
Genetic testing in a person with neuropathy can be beneficial to:
1. establish the genetic cause of neuropathy;
2. provide information about prognosis;
3. possibly prevent the need for other costly and/or painful testing;
4. confirm the inheritance pattern and allow for more accurate risk assessment of family members;
5. permit predictive testing for asymptomatic family members when there is a known disease-causing mutation associated with a genetic form of neuropathy;
6. enable clinical monitoring, follow-up, and optimal treatment when symptoms develop in a person with a positive genetic result;
7. enable prenatal diagnosis for known disease-causing mutations in at-risk pregnancies;
8. allow accurate genetic counseling, determination of the risk of recurrence, and family planning.
Genetic testing reports mutations, or changes in the DNA sequence, associated with disorders caused by single genes.
Chromosomal analyses report abnormalities in chromosomes such as deletions and duplications that may affect one or more genes and are connected with various known syndromes.
What results can I expect from genetic testing, and what do they mean?
There are three possible outcomes of genetic testing: positive, negative, or inconclusive.
Positive: A positive result indicates that a disease-causing mutation was identified in the person tested. This finding confirms the diagnosis as well as identifies the genetic cause. First-degree relatives (e.g., children, siblings, and parents) of a patient with a positive genetic test result can then be offered predictive genetic testing. If a family member is found to be positive for the mutation, they can then be referred to a specialist for preventive management. There can be variability in symptoms, the age at which they appear, and their severity among family members who share the mutation. This is because other genetic and environmental factors, in addition to the identified mutation, can affect a person’s ultimate phenotype.
Negative: A negative genetic test result may mean that the patient does not have a heritable form of neuropathy. However, it does not necessarily rule out any genetic cause – only that the tested genes do not appear responsible. A so-called “false negative” result may come about because a different, affected gene was not included in the testing panel, or the patient may have a mutation in a part of a gene that was not covered by the test.
A negative genetic test result in a person with neuropathy indicates that testing of asymptomatic family members with the same test will not be helpful. Family members of an affected person with negative test results may still be at risk for neuropathy based on the family history.
Variant of unknown significance (VUS): This result indicates that a mutation or variation in a gene has been identified; however, its role in causing neuropathies is not clear. Testing of other family members may help clarify the clinical significance of a VUS. If other relatives with neuropathy are found to have the same variant, the clinician may infer that the variant is causing disease. The greater the number of affected family members who carry the VUS, the greater the likelihood that the identified variant is pathogenic. If, on the other hand, the patient is the only one in the family affected by disease, and did not inherit the VUS from a parent, that supports the interpretation that the VUS is disease causing.
Sometimes a person may be found to have a mutation in just one of two copies of a gene associated with a so-called autosomal recessive disorder. In recessive disorders, mutations are needed in both copies of a gene to cause disease. If only one copy is affected, the testing results are considered inconclusive, and the person may be considered a heterozygous carrier of a single mutated gene copy and a healthy second copy. Or, the person may have a second mutation that was not detected by the test. When a single mutation is identified in an autosomal recessive disorder, it requires clinical signs of the disease for the clinician to make a genetic diagnosis, and additional testing may be warranted.
Interpretation of variants of unknown significance involves multiple steps including:
- reviewing published research on the variant;
- reviewing publicly available and proprietary databases of information on genetic mutations;
- analyzing how frequent the variant is in the population;
- looking at whether the variant is conserved over evolution;
- considering computer models that predict the possible effect of the variant on gene function;
- considering other reported mutations in the gene;
- determining inheritance of the variant and if it matches with who has the disease in a family.
With the rapid growth of genetic testing and research, more information is becoming available on genetic variants every day. It is important to keep the records of your genetic testing results, since the interpretation may change as more information is collected on your particular variants, especially the VUS.
Reporting of incidental findings in clinical exome and genome sequencing
In addition to reports of variants detected in genes associated with neuropathy, results on additional genes may be included in your genetic report. These additional results, while not related to neuropathy, may help your provider to assist you in management and prevention of future disease.
The list of genes reported on is compiled by the American College of Medical Genetics and Genomics (ACMG). This group of experts have published a minimum list of genes to be reported as incidental or secondary findings in genetic tests. The goal is to identify and manage risks for selected genetic disorders where genotype is highly predictive of disease. This report allows providers and medical geneticists to use established tests and interventions aimed at preventing or significantly reducing illness and death from diseases associated with known genetic variants.
These recommendations are designed primarily as an educational resource, and the presence of any particular gene variant does not guarantee the presence of any specific medical condition. In determining the necessity for any follow-up procedure or test, providers need to apply their own professional judgment to the clinical circumstances of the individual patient. The list is regularly updated and currently includes 59 genes recommended for inclusion in clinical genomic sequencing. Each of these genes is considered “medically actionable,” which means that identification of variants suggests additional follow-up by your doctor is appropriate.
You can find more information at the following websites:
Online Mendelian Inheritance in Man (OMIM): Search for Research Studies for Neuropathy