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Updated: Jul 25
Examining Why More Than Half of all Who Have Charcot-Marie-Tooth Disease are not Able to Obtain Genetic Confirmation of Their Disease
There’s a rare and complex inheritable peripheral neuropathy with a confusing name. Called CMT, the disease is also a neuromuscular disease, and it is difficult to diagnose. Doctors rely on symptoms, family history, specialized testing that looks for abnormalities with how the peripheral nerves transmit their signals (nerve conduction study), and genetic testing. Genetic testing, however, often fails to identify the cause for an individual’s CMT, leaving doctors and patients frustrated.
There are many different genetic tests available for CMT. With test names such as “Comprehensive CMT Panel,” Comprehensive Neuropathies Panel,” and “[CMT] Neuropathies Panel,” for example, one would think any of these would find the genetic cause when ordered. With such convincing genetic test names, how is it, then, that genetic testing often fails to reveal the cause of one’s CMT? Here, we will attempt to uncover and understand why this propensity exists and what, if anything, can be done to solve it.
Charcot-Marie-Tooth disease (CMT) is a complex heterogeneous rare inherited neuromuscular peripheral polyneuropathy. First described in 1886 by the three doctors whose names this disease bears, Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England, the cause was not found for more than another 100 years, in 1991 (Raeymaekers, et al., 1991). Leading up to this monumental genetic discovery, scientists knew CMT was inheritable and therefore had a genetic component, and they predicted there might be four or five causes for CMT. The initial genetic discovery, however, was only the beginning.
As of today, scientists have discovered CMT-causing mutations in 128 individual genes (Experts in CMT, 2023). Additionally, scientists have mapped four potential CMT causes to four chromosomal locations, but the exact gene remains elusive. Combined, these account for 162 individual CMT subtypes. Despite the enormity of the number of CMT-causal genes thus far discovered, scientists believe they could very well be only halfway to discovering all genetic causes for CMT (Shy, 2020).
Clinically, CMT is divided into CMT1 and CMT2 according to nerve conduction study results (Dyck, Lambert, & Mulder, 1963). Statistically, approximately 95% of all individuals who have demyelinating CMT (CMT1 clinical diagnosis) can today obtain a genetic confirmation of their CMT. In sharp contrast, only about 50% of individuals who have an axonal CMT (CMT2 clinical diagnosis) can obtain a genetic confirmation, and some believe this might be as low as only 30% (Züchner, 2021) (Shy, 2020). Combined, less than half of all who have CMT can today obtain genetic confirmation of their clinical diagnosis.
Current data modeling depicts that 1 out of every 2,500 people in the world have CMT (Inherited Neuropathies Consortium (INC), 2021). This modeling accounts for both diagnosed and undiagnosed cases. The model predicts that 0.04% of the global population has CMT, even if they’re not yet diagnosed. We can use this model to estimate how many CMTers can obtain genetic confirmation versus how many cannot.
The Likelihood of Obtaining Genetic Confirmation
There are approximately 8 billion people in the world today (United States Census Bureau, 2023). This means approximately 3.2 million people have CMT, even if they don’t yet know it. Using the probability of obtaining genetic confirmation statistics previously discussed, approximately 28.5% to approximately 47.5% of CMTers can obtain genetic confirmation, equating to between approximately 912 thousand and 1.5 million CMTers while between 1.7 million and 2.28 million CMTers are not able to obtain confirmation, globally. In the US, which has a population of approximately 334 million, there are about 134,000 CMTers. Between approximately 38,000 and 63,000 can obtain genetic confirmation while between 71,000 and 95,000 cannot.
Statistically, a CMT genetic test is more likely to fail at identifying a genetic cause for one’s CMT than the test is to genetically confirm CMT, and this is due to the limitations of CMT genetic testing. These limitations are predicated, in part, on the statistical variables we’ve thus far discussed. Additionally, the genes that make up the chosen test panel is another variable to account for.
The Variability of Commercially Available CMT Genetic Test Panels
CMT genetic testing has long been commercially available. There are many laboratories offering various gene panels for CMT. A gene panel is a genetic test that looks at more than one specific gene as part of the test. Everything from a basic three or four gene panel up to and including a panel with 153 genes are readily available. Some of the smaller panels, for example having four genes to as many as 60 genes, include genes in which every gene on the panel has linkage to CMT. Getting into the larger ones, panels having more than eighty genes, for example, often include genes that have no CMT linkage. This is another part of the problem CMTers face for obtaining genetic confirmation of their disease.
The most popular and/or largest CMT genetic test panels commercially available are compiled with an impressive list of genes on their respective panels. However, a review of these panels reveal each is limited insofar as they exclude sometimes dozens of CMT-related genes. Also, each respective panel has genes the others do not.
Laboratories, regardless of which genetically caused disease they are offering testing for, have the ability to add genes to their panels that meet the needs of the patient community. The genetic testing industry in the US is largely unregulated though (NIH, 2022). There isn’t a standard that genetic testing companies must adhere to for gene inclusion on their respective panels. Genetic testing companies are able to make the decisions for themselves, and understandably so.
According to Carly Siskind, MS, CGC, who is a certified genetic counselor at Stanford University Department of Neurogenetics and Neurogenomics, and who is a leading CMT genetics expert, there isn’t a commercial laboratory that offers a gene panel that includes all known CMT-related genes. The specific test ordered plays a large role in testing outcomes—not all panels are created equally. Says Siskind, “this is one of the toughest hurdles I have when trying to obtain a genetic diagnosis for my CMT patients.”
Examining the Data
The following tables provide an exhaustive list of all CMT-related genes discovered and published as of March 6, 2023, and an itemized breakdown of three CMT genetic test panels: Invitae’s Comprehensive Neuropathies Panel test 03200 (Invitae Comprehensive Neuropathies Panel, 2022), GeneDx’s Hereditary Neuropathies Panel test 737 (GeneDx Hereditary Neuropathies Panel Test Code: 737, 2022), and Blueprint Genetics’ Charcot-Marie-Tooth Neuropathies Panel test NE1301 (Blueprint Genetics, 2022).
The gene list for each panel is given, and on each panel, the genes linked to CMT are marked in red and with an asterisk (*). Following the three panels are itemized analyses comparing each of the three panels to one another, and a datapoint for each that gives the CMT-related genes excluded by the panel.
The Invitae Comprehensive Neuropathies panel has an option to add nine additional genes. The following data are based on the panel’s standard 102 genes without the optional add-ons. The exhaustive list of CMT-causal genes includes an “aka” in parenthesis for genes that appear on the subsequent panels with an older name.
The HUGO Gene Nomenclature Committee is the governing body for curating gene names and their symbols. The exhaustive list of genes displays the currently approved HGNC gene symbol (abbreviation) for each gene. Not all genes on the following panels have been updated to the latest HGNC approved symbol by the respective laboratory, and any discrepancy is superficial based on this.
Invitae 03200: 85 genes with linkage to CMT**
GeneDx 737: 82 genes with linkage to CMT
Blueprint Genetics NE1301: 97 genes with linkage to CMT
Invitae 03200 genes not on GeneDx 737 (11 genes):
ATP1A1, DCTN1, DHTKD1, DRP2, FBLN5, MARS1, MCM3AP, PMP2, POLG, SURF1, UBA1
Invitae 03200 genes not on Blueprint Genetics NE1301 (4 genes):
DRP2, SIGMAR1, SLC5A7, VRK1
GeneDx 737 genes not on Invitae 03200 (8 genes):
ABHD12, CNTNAP1, KARS1, MPV17, PNKP, SCO2, SETX, VCP
GeneDx 737 genes not on Blueprint Genetics NE1301 (6 genes):
ABHD12, CNTNAP1, SCO2, SIGMAR1, SLC5A7, VRK1
Blueprint Genetics NE1301 genes not on Invitae 03200 (15 genes):
ARHGEF10**, ATP6, CCT5**, COA7, CTDP1, DCAF8, HADHB, HK1, KARS1, MPV17, MTRFR, PNKP, SCYL1, SETX, VCP
Blueprint Genetics NE1301 genes not on GeneDx 737 (20 genes):
ARHGEF10, ATP1A1, ATP6, CCT5, COA7, CTDP1, DCAF8, DCTN1, DHTKD1, FBLN5, HADHB, HK1, MARS1, MCM3AP, MTRFR, PMP2, POLG, SCYL1, SURF1, UBA1
Invitae 03200 genes not on either GeneDx 737 or Blueprint Genetics NE1301 (1 gene):
GeneDx 737 genes not on either Invitae 03200 or Blueprint Genetics NE1301 (3 genes):
ABHD12, CNTNAP1, SCO2
Blueprint Genetics NE1301 genes not on either Invitae 03200 or GeneDx 737 (10 genes):
ARHGEF10**, C12ORF65, CCT5**, COA7, CTDP1, DCAF8, HADHB, HK1, MT-ATP6, SCYL1
Genes on all three of these panels (721genes):
AARS (aka AARS1), AIFM1, ATL1, ATL3, ATP7A, BAG3, BICD2, BSCL2, CHCHD10, COX6A1, DNAJB2, DNM2, DNMT1, DST, DYNC1H1, EGR2, ELP1, FBXO38, FGD4, FIG4, GAN, GARS (aka GARS1), GDAP1, GJB1, GNB4, HARS (aka HARS1), HINT1, HSPB1, HSPB8, IGHMBP2, INF2, KIF1A, KIF5A, LITAF, LMNA, LRSAM1, MFN2, MME, MORC2, MPZ, MTMR2, NDRG1, NEFH, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRDM12, PRPS1, PRX, RAB7A, REEP1, RETREG1, SBF1, SBF2, SCN11A, SCN9A, SEPT9, SH3TC2, SLC12A6, SLC25A46, SPG11, SPTLC1, SPTLC2, TFG, TRIM2, TRPV4, WNK1, YARS (aka YARS1)
Genes not on Invitae (43 genes):
ABHD12, ARHGEF10**, ATP6 (aka MT-ATP6), C19ORF1, CADM3, CCT5**, CFAP267, CNTNAP1, COA7, CTDP1, DCAF8, DGAT2, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, HADHB, HK1, HSPB3**, ITPR3, JAG1, KARS1, MPV17, MTRFR (aka C12ORF65), MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, PNKP, POLR3B, PSAT1, SCO2, SCYL1, SETX, SORD, SGPL1**, SYT2, TUBB3, UBE3C, VCP, VWA1, WARS1
Genes not on GeneDx (46 genes):
ARHGEF10, ATP1A1, ATP6 (aka MT-ATP6), C19ORF12, CADM3, CCT5 CFAP276, COA7, CTDP1, DCAF8, DCTN1, DGAT2, DHTKD1, DRP2, FBLN5, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, HADHB, HK1, HSPB3, ITPR3, JAG1, MARS (aka MARS1), MCM3AP, MTRFR, MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, PMP2, POLG, POLR3B, PSAT1, SCYL1, SGPL1, SORD, SURF1, SYT2, TUBB3, UBA1, UBE3C, VWA1, WARS1
Genes not on Blueprint (32 genes):
ABHD12, C19ORF12, CADM3, CFAP276, CNTNAP1, DGAT2, DRP2, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, HSPB3, ITPR3, JAG1, MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, POLR3B, PSAT1, SCO2, SGPL1, SIGMAR1, SLC5A7, SORD, SYT2, TUBB3, UBE3C, VRK1, VWA1, WARS1
Genes not on any of these 3 panels (23 genes):
C19ORF12, CADM3, CFAP276, DGAT2, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, ITPR3, JAG1, MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, POLR3B, PSAT1, SORD, SYT2, TUBB3, UBE3C, VWA1, WARS1
The three example panels and their differences perfectly illustrate the limitations inherent in conventional CMT genetic testing. These limitations are why a genetic test result that fails to provide a clear straightforward confirmation of the clinical CMT diagnosis means only that the gene with the responsible mutation has yet to be tested for and a result like this does not mean CMT is ruled out.
**Invitae 03200 optional nine additional genes adds the CMT genes ARHGEF10, CCT5, HSPB3, and SGPL1 to the panel.
Beyond The Conventional Panel
Gene panels for CMT genetic testing are the standard go-to. A gene panel is a genetic test that looks at more than one gene during a test, but the genes being looked at are the specific genes listed on the panel and nothing beyond these, whether there are only two genes on the panel or hundreds. When a gene panel doesn’t reveal a clear straightforward genetic confirmation of the clinical CMT diagnosis there are more sophisticated genetic tests available as next-step options.
When conventional genetic testing is exhausted and obtaining a genetic confirmation of the clinical CMT diagnosis didn’t happen, the next step is Whole Exome Sequencing (WES). WES is a sophisticated and expansive genetic test. WES sequences the entire genome—all 20,000+ genes, then attempts to look at all coding regions of every gene—the exons. Hence “exome.” A gene has two basic parts: the exon which holds all coding genetic material, and the intron which holds all non-coding genetic material.
What is Whole Exome Sequencing (WES)?
WES attempts to look at the coding material of all genes to identify disease-causing mutations. Coding, in this context, means the part of each gene that encodes something; and encode means instructs, controls, defines, builds, etc., something within a cell, whether that be an enzyme, a protein, etc. If we think of each gene as a recipe, the coding material is the ingredients, and the cooking instructions are how the gene “encodes.” For example, the SORD gene encodes (cooks, makes) the sorbitol dehydrogenase (dee-hydro-geh-nace) enzyme, and the gene makes this enzyme based on the ingredients (the coding material) of the gene. How the order of the SORD gene’s ingredients are listed (the sequence) determines how the recipe is cooked, (cooking instructions, encodes) and the sorbitol dehydrogenase enzyme is the result, just like following a recipe for chocolate chip cookies results in chocolate chip cookies.
When a doctor orders a WES, they include symptom and condition information with the order. For example, this might look like “history of foot drop, sensory loss, muscle atrophy, suspected Charcot-Marie-Tooth disease.” Once the laboratory sequences the individual’s DNA, the sequenced data is captured by a computer program. Clinicians then input as keywords into the computer program the symptom and condition information provided with the doctor’s order. The computer program then compares this keyword information against genes that are known to have mutations that cause conditions that match the keywords and generates a list of matching genes. This list is referred to as the “primary gene list.”
After the computer program renders the primary gene list, each gene on the list is analyzed for mutations. Any mutations that are identified are then verified by clinicians and genomic scientists at the laboratory. When identified mutations are either known causes (pathogenic) or potentially known causes for conditions matching the input keywords, the mutations are reported in the results. Mutations that are known to be benign and harmless generally are not reported. Although WES attempts to look at all genes rather than only certain genes listed on a panel, there are limitations to WES in the context of CMT.
The Limits of WES
A significant limitation of WES results is “coverage depth,” or how well each gene is reliably analyzed. Some laboratories have greater coverage depth than others, and this drives overall outcome potential. Another significant variable governing the limitations of WES’s ability to reveal an individual’s CMT cause is the symptom and condition information provided by the doctor with the order. If these are too vague, WES’s rendered primary gene list might not capture the gene with the CMT-causing mutation. As equally significant, if the laboratory doesn’t know that a gene has been discovered to have CMT-causing mutations (these discoveries are not reported to, tracked by, or recorded by any entity, agency, or organization), the gene will not be included in the primary gene list and then analyzed for potential CMT-causing mutations. When this happens, the results might not truly represent an individual’s genetic profile, and just like when conventional gene panels fail to reveal a cause of CMT, a WES result that fails to reveal the CMT cause means only that the gene with the CMT-causing mutation was not looked at, and the result means only this.
When WES fails to reveal the CMT cause, another test, Whole Genome Sequencing (WGS), is the next and final option. WGS is performed just like WES, but WGS goes beyond only the coding regions of each gene and looks at all parts of the gene. WGS is used only for research purposes at the present time. In the context of CMT, WGS is also bound by the same limitations as WES. For diagnostic purposes, WGS, at the present time, doesn’t provide much of a diagnostic advantage over WES. This is likely to change, however, as technology grows, and as genomic science understandings evolve.
Why test with so many limitations in CMT genetic testing and with results that are statistically more likely to be negative or inconclusive?
To Test or Not to Test?
CMT genetic testing is a personal choice. For some, the decision is based on treatment availability. “If I can’t treat it, why test for it?” is a common view in the CMT community. Many healthcare providers feel the same way. Additionally, if there is a higher likelihood for a negative genetic test result than there is for a positive test result, “why should I bother?” These are valid feelings about CMT genetic testing.
Often, the decision to not test is based on prohibitive out-of-pocket costs whether the costs are from insurance coverage denials or from an absence of healthcare coverage. Other times, testing just isn’t convenient with having to go to an outpatient lab for a blood draw. Sometimes, these things result from a lack of healthcare provider awareness regarding available CMT genetic testing options. Modern testing is now performed with simple at-home saliva collection with a cheek swab, and this overcomes some of these issues.
Many CMTers and their healthcare providers become frustrated by CMT genetic test results that fail to confirm the clinical diagnosis. For a healthcare provider, the lack of genetic confirmation means the diagnostic puzzle is that much more difficult to piece together. In a survey of 100 CMT patients who have a clinical diagnosis but have been unable to obtain genetic confirmation, 97% said they feel like they lack a “real diagnosis,” and 89% say their negative genetic test result is preventing them from attaining closure. These things are understandably frustrating. For some, seeing this frustration in the community fosters an unwillingness to attempt genetic testing, and rightfully so—in the survey, 37% said the chances of a negative test result is sufficient enough to not bother with testing.
The reasons to forego CMT genetic testing are many and are as diverse as are the individual CMTers. The above examples from the CMT patient community, from the healthcare community, and from the survey results are just a few reasons that drive decisions to not test. Where CMT genetic testing might not reveal the genetic cause for the CMTer, there is still a chance it will reveal that cause.
Obtaining genetic confirmation of one’s CMT means knowing the exact subtype. Knowing the exact subtype means knowing the subtype’s inheritance pattern—how CMT can be passed on and the chances that it will be passed onto the CMTer’s children. This is important for family planning, if not for the CMTer, then for the CMTer’s children when they’re ready to start their own family.
Having genetic confirmation often means meeting criteria for clinical trials. CMT clinical trials are almost always subtype specific. Investigators trialing a drug, or a gene therapy, are targeting a specific genetic cause that applies only to the related subtype. For this reason, genetic confirmation is needed for trial participation (Record, et al., 2023).
Much like the reasons to not test, the reasons to test are many and are as diverse as are the individual CMTers. The reasons to test, however, are not limited to only the prospect of a confirmatory test result. Results that fail to overtly identify a genetic cause for one’s CMT are as equally important as results that do confirm, and they are perhaps even more important.
When Genetic Testing Fails
So much in CMT relies on a genetic confirmation. In this context, confirmation means confirming the clinical CMT diagnosis. Genetic confirmation in CMT, however, is the exception, not the rule. If genetic confirmation is not possible for so many who have CMT, then how are they to know for certain they even have CMT? As it turns out, genetic testing is not needed to diagnose CMT.
Richard A. Lewis, MD is a Professor of Neurology at Cedars-Sinai Medical Center and is the Director of the Charcot-Marie-Tooth Association’s (CMTA) Center of Excellence CMT Clinic at Cedars-Sinai. Dr. Lewis explains that genetic testing is but only one piece of the diagnostic picture doctors consider when diagnosing CMT (Raymond, 2021). According to Dr. Lewis, symptoms, family history, and nerve conduction study results all play an equal role when diagnosing CMT, and together, often inform the doctor's genetic testing decisions.
To diagnose CMT, says Dr. Lewis, “one needs the appropriate clinical picture—numbness and weakness in the feet and usually in the hands occurring with reduced reflexes, plus a family history of the same problems that cannot be due to other causes such as diabetes. Also, the nerve conduction studies should show evidence of neuropathy—nerve conduction velocities that are very slow fit a diagnosis of CMT1 [clinical CMT1 diagnosis], and if not very slow, CMT2 [clinical CMT2 diagnosis].” Dr. Lewis continues, “having pes cavus (high arches) since early in life is supportive evidence of a CMT diagnosis. But other neuropathies can give a similar clinical picture and similar nerve conduction study findings.”
Dr. Lewis also explains that “an abnormal genetic test with the right mutation in the right gene would be proof it’s CMT. However, genetic testing doesn’t always detect a problem and that doesn’t mean that a genetic disorder such as CMT is not the cause.” “In addition,” Dr. Lewis says, “genetic testing results can be difficult to interpret and can be confusing to the patient.” A definitive diagnosis depends on a doctor putting all the diagnostic information together; and, it is important not to miss a treatable cause of neuropathy. With all of this complexity in mind, Dr. Lewis advises that it is best to get a good neurologic evaluation if you have neuropathy.
The Significance of a Negative CMT Genetic Test Result
A CMT genetic test result that comes up empty can be gut wrenching for the CMTer, especially when all genetic testing options have been exhausted. There’s no question about that. It’s an unfortunate reality for so many. At face value, this outcome might seem like testing was a waste of time. Nothing could be farther from the truth though. A negative test result is just as important as a positive result, and perhaps even more important.
Laboratories store genetic test sequenced genome data. Data? Once the lab sequences a genome (genome = DNA), all the genetic information is input into a computer program. The computer program then renders this sequenced information into a structured data file that can be stored, analyzed, and compared against in the future. This is the important part in the context of CMT.
The Distant Cousin Project
CMT genetic discoveries happen, in part, because scientists can analyze and compare many different genomes from many different CMTers. The Genesis Project is one such organization that is actively engaged in identifying undiscovered genes that hold CMT-causing mutations. The work conducted by the Genesis Project has thus far resulted in more than 100 rare disease genetic discoveries (The Genesis Project, 2022). Some of these discoveries are genes with linkage to CMT, including the monumental SORD-deficiency CMT discovery (Cortese, et al., 2020).
The Genesis Project Foundation was co-founded and is chaired by Stephan Züchner, MD PhD, who is a geneticist at the University of Miami. Dr. Züchner has dedicated his working life to identifying unknown genetic causes of rare diseases. Among his genetic discovery credits are dozens of genes with linkage to CMT. Dr. Züchner has many active research projects that are focused on finding undiscovered culprit genes for rare diseases. A culprit gene is a gene that has a disease-causing mutation. One such project focusing on CMT is the Distant Cousin Project.
What is the Distant Cousin Project? The Distant Cousin Project, Dr. Züchner explains, is a genetic research project whose purpose is to identify CMT culprit genes by analyzing the genome of a CMTer and a distant cousin who also has CMT, then comparing the two genomes to find identical gene mutations that could potentially explain their CMT. Why a distant relative and not a parent or sibling? The answer might surprise you.
Dr. Züchner explains, “Intuitively, it might seem that having one’s genome and the genomes of close family members with the same disease sequenced should lead to a discovery of the culprit. To some extent, that’s true.” This makes sense. This seems very straightforward and fairly simple. However, Dr. Züchner continues, “The problem is that researchers can readily identify hundreds of potential culprit variants (variations of unknown significance) in many genes in nearly every genome studied. One shares too much DNA with close relatives to narrow the genes down to just a few possibilities.” This is where the Distant Cousin Project comes in.
The foundational basis of the Distant Cousin Project is to look at the CMTer’s genome and that of a distant cousin, perhaps a 3rd or 4th cousin, if the CMTer has or can locate such a distant relative, then compare the two. Unlike close relatives such as parents and siblings who share many of the same genetic mutations, “4th cousins share only about one-fifth of one percent of their DNA,” explains Dr. Züchner. “If two 4th cousins share the same culprit gene,” Dr. Züchner continues, “there is a very good chance that researchers could locate it.” Dr. Züchner also cautions that such distant relatives, who both have CMT, might have different genetic causes from each other.
Dr. Züchner is conducting the Distant Cousin Project research study through his work at the University of Miami and the participant genomes will be analyzed by The Genesis Project. There has already been a successful outcome. Through this study, Dr. Züchner and his team of researchers have identified mutations in the ITPR3 gene that are causing a CMT1 subtype. Dr. Züchner explained that two large families, one family from Wisconsin and one from Sydney, Australia were the key for this discovery, and the discovery was made possible by their participation in the Distant Cousin Project. CMT1J has emerged as the subtype name for this discovery (Kniffin, 2022).
Dr. Züchner’s study is limited to ten families, and the study is currently enrolling participants. To be considered, the CMTer, one of their parents, and the distant cousin must have a clinical CMT diagnosis preferably from a recognized CMT expert clinic and each must have unsuccessful genetic testing outcomes. Although a daunting task for many, the CMTer must have located the distant cousin prior to enrolling in the study. The study provides the related genomic analysis at no cost to the participants. If you’d like to be considered for the study, you can send an email to study coordinator, Yeisha Arcia, at email@example.com.
The Distant Cousin Project is just one example of how negative CMT genetic test results are intrinsically important to CMT research and this example perfectly illustrates the importance of undergoing genetic testing regardless of the outcome – study participants must first have failed CMT genetic testing before they are eligible for the study. The study might then lead to identifying the culprit gene and its responsible CMT-causing mutation, and the discovery might stand the CMT world on its head. One such discovery made possible by the genomic database work of Dr. Züchner and The Genesis Project, the SORD-deficiency CMT discovery, did just that.
Combing heaps of genomic data curated by The Genesis Project, Dr. Züchner and his team of investigators at the University of Miami made a discovery that has changed the course of CMT treatment research. Analyzing a collection of genomes from CMTers who had undergone unsuccessful genetic testing, the investigators discovered mutations in the SORD gene in several of the genomes and were able to conclude these were a cause for CMT. Cortese et al., 2020 dubbed this new CMT subtype discovery “SORD-deficiency.” What makes this discovery so special?
Very quickly, researchers learned that an estimated 3,000 CMTers in the US, 4,000 CMTers in Europe, and an estimated 60,000 CMTers worldwide have this CMT subtype (Shendelman, 2022). SORD-deficiency CMT is the most commonly occurring autosomal recessive axonal subtype. Prior to genetic confirmation, CMTers who have this subtype are/were clinically diagnosed with CMT2 or the CMT classification dHMN (Distal Hereditary Motor Neuropathy). This discovery wouldn’t have been possible if the many CMTers whose genomes led to the discovery hadn’t undergone genetic testing that resulted in a negative outcome. But why is this discovery so important.
The SORD gene encodes an enzyme called sorbitol dehydrogenase. The mutations in the SORD gene that cause CMT cause this enzyme to be either nonfunctioning or absent altogether. The result is CMT. Due to the hard work of many scientists, researchers, and investigators, both from within CMT and outside of CMT, expertise with therapies targeting the sorbitol dehydrogenase enzyme was identified. With so many working together, this expertise, developed by a biopharma company named Applied Therapeutics, adapted an investigational sorbitol dehydrogenase targeting therapy to the needs of the newly found SORD-deficiency CMT community.
Just two years after the SORD-deficiency discovery, there was a Phase III clinical trial underway investigating a treatment for this CMT subtype (Applied Therapeutics, 2022). Now, almost three years after discovery, preliminary data from this clinical trial released by Applied Therapeutics show very promising results as a potential viable treatment for this subtype (SORD-CMT INSPIRE Trial, February 2023 Preliminary Data Release, 2023). “Examples like SORD,” explains Dr. Züchner, “show how genomic discovery increasingly can result in direct pathways to treatment trials.”
Solving the Unsolvable
The reasons why so many CMTers are unable to obtain genetic confirmation of their CMT, are unable to obtain that coveted genetic diagnosis are many. A significant factor in testing outcomes is the specific test the doctor orders. A review of available data from the websites of the companies whose panels we analyzed shows striking differences between each, yet each has capabilities the others do not, meaning each can potentially result in a genetic confirmation that’s not possible with the others. Which is best? “That depends,” seems to be the best answer.
The genetic test panels used in CMT are part of the problem because of so much variability between the panels and because of the panel names themselves. One such panel, titled, “Charcot-Marie-Tooth Disease Comprehensive Panel,” infers the test should yield the best possible test outcome. However, there are only 57 genes on the panel (Invitae Charcot-Marie-Tooth Disease Comprehensive Panel, 2022). The company offers an optional three genes to add to the test. Even at 60 genes, this is less than half of all known genes discovered to have CMT-causing mutations. While these panels are part of the problem, the respective companies who offer CMT genetic testing are also the solution.
Companies offering CMT genetic testing have to do better with panel design. CMT genetic discoveries move fast. All data presented in this article are publicly available. When scientists make CMT genetic discoveries, they publish their findings in peer-reviewed journal articles. If the paper itself is not fully publicly available, the abstract is in the very least. Three years after the SORD discovery, the most common autosomal recessive axonal CMT, the gene is not on any CMT genetic testing panel. The ability for a testing company to learn of new discoveries is there. The companies must then adjust their CMT panels accordingly. The patient community, the healthcare community, the research community, and the biopharma community need this. Health and well-being depend on this. The patient community has a responsibility to the solution, also.
A negative CMT genetic test result, as frustrating as it might be, is a significant part of the solution to the problem of less than half of all who have CMT not being able to obtain genetic confirmation of their disease. Closing this gap requires CMTers to participate in genetic testing. Researchers who are working to find unknown genetic causes need genomes from CMTers who have negative genetic test results. This means that, when genetic testing fails to reveal the cause, the patient needs to contact researchers like Dr. Züchner and have their genome (DNA) added to a database that researchers are continually analyzing.
Patient advocacy groups are also part of the solution. Patient advocacy groups provide research funding that supports genetic discoveries in CMT. These groups, such as the HNF and the CMTA, for example, are authoritative bodies within the CMT space. These groups, and others, are perfectly positioned to generate the needed awareness among the patient and healthcare communities around the need for genetic testing, and especially the importance of a negative test result, and then who to contact with that result. The Hereditary Neuropathy Foundation (HNF) has a fantastic program called CMT Genie that leads CMTers to CMT genetic testing when they otherwise wouldn’t have access to testing, and this program is creating the needed awareness.
As complex of a problem as CMT genetic testing is, the problem is solvable. Solving this problem will require everybody in the CMT community working together. The CMT community has many moving parts, and each are integral to overcoming the limitations of genetic testing that are inherent in CMT.
Gene discovery in CMT continues to grow. Today, scientists have discovered 128 genes to have CMT-causing mutations. During the research for this article, we learned of two very recent gene discoveries in CMT that aren’t published yet (these are not part of the data analysis). Without publication, commercial labs don’t know to even consider the genes for inclusion on their panels.
In a recent conference I attended, Steven S. Scherer, MD, PhD, a renowned CMT clinician and researcher who has many CMT gene discoveries to his credit, suggested [we’ll] cross the 200 genes mark by . With the rates of annual gene discovery in CMT, he’s spot on. If Dr. Shy is right, crossing the 200 gene mark doesn’t get us to the finish line, but is only another lap out of an undetermined number of needed laps in this race though.
When first described in 1886 by Drs. Charcot, Marie, and Tooth, CMT was a simple disease affecting only the lower legs. CMT, however, has no doubt emerged as perhaps one of the most complex diseases the medical science community has on their plate. Unfortunately, this complexity results in many who have this disease begging for answers but finding only more questions.
The need for CMT patients to undergo genetic testing has never been greater. Currently, there is no effective treatment nor a cure for the disease (Cipriani, et al., 2023). Genetic confirmation helps with identifying a patient population treatment researchers and biopharma researchers need for studying potential therapies. At the same time, negative results are even more important because these provide a crucial opportunity for researchers to obtain vital genomes from CMTers in hopes of discovering new causes of CMT. A single genome submission from a CMTer who had a negative genetic test result can potentially affect thousands if their DNA leads to researchers finding a new cause for CMT. This has happened with the SORD-CMT discovery, and it could very well happen again.
About the Author
Kenneth Raymond was first diagnosed clinically with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has since devoted his life to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. Currently pursuing an MS in Genetics, Cell, and Developmental Biology at Arizona State University, Kenneth’s passion for understanding CMT and improving the lives of those who are living with CMT remains as strong as ever.
Conflicts of Interest:
The author declares that he is employed by the Hereditary Neuropathy Foundation (HNF) and is a paid consultant of the Charcot-Marie-Tooth Association (CMTA).
CMT Gene Discovery, CMT Genetic Testing, Patient Resources, and Clinical Research
The Genesis Project Foundation:
The Hereditary Neuropathy Foundation:
The HNF CMT Genie Program Connecting Patients to CMT Genetic Testing:
The Hereditary Neuropathy Foundation Global Registry for Inheritable Neuropathy - GRIN:
HNF's Natural History Study for CMT - ClinicalTrials.gov ID NCT05902351
The Charcot-Marie-Tooth Association:
The CMTA's Patients as Partners Research Registry
The CMT Research Foundation:
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