Genetic study reveals new mutations linked to CMT – Charcot-Marie-Tooth News
New genetic analysis tools have identified previously unknown genetic mutations in people diagnosed with various types and subtypes of Charcot-Marie-Tooth (CMT) disease, a study reveals.
New techniques used to discern different genes and rare variants could allow researchers to improve detection rates for this neuropathic disorder.
The study, “Cohort analysis of 67 Italian Charcot-Marie-Tooth patients: identification of new mutations and broadening of phenotypic expression produced by rare variantswas published in the journal Frontiers in genetics.
CMT is a group of inherited diseases caused by mutations in genes that affect the function of peripheral nerves, which lie outside the brain and spinal cord and control movement and sensory function.
Although the most common genetic alteration causing the disease is a duplication of the PMP22 about 100 different genes have been associated with a wide variety of disease characteristics.
As such, there are different types and subtypes of CMT which are categorized based on specific defective genes, how they are inherited, age of disease onset, disease severity and the speed of electrical impulses along nerve fibers.
Despite the availability of genetic analysis, not all genes associated with CMT have been identified.
New technologies, such as next-generation sequencing (NGS), can analyze hundreds of genes in a single experiment and help identify new genes and mutations (variants) associated with CMT. Another technique known as multiple ligation-dependent probe amplification (MLPA) can detect variations in gene copy number, such as PMP22 reproduction.
In this observational study (NCT03084224), a team of Italian researchers applied these genetic analysis techniques to a group of 67 unrelated patients with CMT to identify genetic characteristics associated with their condition.
The diagnosis of CMT was based on progressive nerve damage, or neuropathy, with or without a family history after excluding other acquired causes of neuropathy. Subtypes were diagnosed based on whether motor or sensory nerves (or both) were affected, as was nerve impulse velocity. Blood samples were taken and genomic DNA from isolated immune cells was extracted and analyzed.
MLPA experiments have found variations in the number of PMP22 gene copies in 26 of 67 participants (38.8%). Of these, 20 participants had everything PMP22 gene duplications in one of the two copies of genes inherited from their parents (heterozygotes). These results confirmed a diagnosis of CMT type 1A (CMT1A), the most common subtype of CMT1, which is characterized by damage to the myelin sheath that surrounds nerve fibers.
Another patient diagnosed with CMT1A carried an additional copy of PMP22 due to mosaic duplication, characterized by additional genetic material. In five patients, the PMP22 The gene was missing, which confirmed the alternative diagnosis of hereditary neuropathy with pressure paralysis (HNPP), a similar condition that also affects peripheral nerves.
NGS tested the remaining 41 participants against a panel of 49 CMT-associated genes. The results identified eight pathogenic (disease-causing) or probably pathogenic mutations in the 41 cases (19.5%) or nearly 12% of the 67 patients.
“Thus, NGS improved the detection rate to 50.8% (38.8% MLPA + 12% NGS),” the team wrote.
Age of disease onset in all individuals with an identified genetic defect ranged from 7 to 57 years, with clinical features consistent with known disease characteristics.
The eight genes with CMT-related mutations included MFN2, MPZ, GDAP1, SH3TC2, HSPB1, KIF5A, MTMR2and KIF1A. Five of these genetic defects impact myelin, while the other three are associated with damage to either nerve fibers directly (axonal) or nerve fibers and myelin. Three variants had been previously reported; five were unknown.
The families of six of the eight participants with these genetic defects were available for further analysis. The mutations were classified as sporadic in three of the eight cases, and familiar in five.
Of the sporadic cases, based on the absence of mutations or disease in the parents, one occurred in a 45-year-old woman due to a mutation in the MFN2 gene responsible for the diagnosis of axonal CMT2A. A 45-year-old man wore a MPZ genetic mutation that caused CMT dominant intermediate D disease, a rare form of CMT with axonal and demyelinating neuropathy.
The third case was a 76-year-old woman who had a mutation in the HSPB1 gene, previously associated with the familial form of the neurological disease amyotrophic lateral sclerosis (ALS). Its mutation caused type 2F axonal CMT.
Of the five cases caused by familial CMT, one was a 67-year-old man with a previously unknown disease KIF1A variant, which was considered probably pathogenic due to an affected sibling. This variant caused CMT2C, a rare form of CMT, which is also caused by mutations in the TRPV4 uncomfortable. A 69-year-old man with axonal neuropathy was discovered via a new mutation in the GADP1 gene responsible for CMT2K. Her sister had a similar condition, but she was not tested.
The third familiar patient was a 45-year-old man with demyelinating disease and known mutations in both SH3TC2 copies of genes, which caused CMT4C. Both parents were healthy carriers of these variants. A 60-year-old man was the fourth case due to a previously unknown mutation in KIF5A, which is also associated with ALS. He was diagnosed with a similar condition called spastic paraplegia, and this variant was present in his affected sister but absent in a healthy sister.
The fifth familiar patient was a 30-year-old woman with axonal neuropathy caused by a new mutation in both MTMR2 copies of genes. He was classified as probably pathogenic due to his affected brother, who also carried this defect, and caused CMT4B1. His parents were carriers.
Finally, seven variants of uncertain significance (VoUS), whose function is still unknown, were found in six of the 67 participants. In these cases, there was insufficient evidence that these mutations were associated with their CMT, or family members were not available for testing.
“This cohort [group] The analysis demonstrates the importance of combining different molecular approaches to identify the causative variant in patients with CMT,” the scientists concluded. “Use of the 49-gene NGS target panel identified causative variants in eight patients, improving the detection rate to 50.8%.”
“Therefore, these approaches allow the identification of new genes and rare variants, thereby improving the rate of genetic detection,” they added.