New Gene Testing Tools Like WES Help in Diagnosing Rarer CMT Subtypes, Case Series Reports

New genetic technologies like whole-exome sequencing can be used to more quickly diagnose specific subtypes of Charcot-Marie-Tooth disease (CMT), helping patients avoid unnecessary treatments, a recent case series reports.

The study, “Whole exome sequencing establishes diagnosis of Charcot–Marie–Tooth 4J, 1C, and X1 subtypes,” was published in the journal Molecular Genetics & Genomic Medicine.

CMT can be caused by mutations in more than 80 different genes. The most common is a duplication in a gene called PMP22, which causes CMT type 1 subtype A (CMT1A) and accounts for about a third of all CMT cases. Yet, this also means that the majority of cases are caused by mutations in other genes, hindering diagnosis.

The advent of next generation sequencing (NGS) technologies may overcome such diagnostic obstacles.

Whole-exome sequencing (WES) is a type of NGS that is designed to sequence only the parts of the genome (all genes present in our DNA) that code for proteins, called the exome. This accounts for less than 2% of the total genome, which makes WES a more efficient and economical alternative to whole-genome sequencing.

This study describes the cases of three people in Greece who, after many years of failed attempts, were correctly diagnosed by CMT subtype using WES.

The first patient was a 66-year-old man who had been experiencing progressive muscle weakness and shrinkage in his legs and arms over a period of 20 years, before a final diagnosis.

When he was first seen by a neurologist after his symptoms started, CMT was suspected. However, when genetic tests failed to identify mutations in PMP22, no definitive diagnosis was made. Subsequently, he was wrongly given possible diagnoses of disorders that include multiple system atrophy, stiff person syndrome, and spastic paraparesis.

WES performed 12 years after the first round of genetic tests revealed he had mutations in both copies (one inherited from each parent) of the FIG4 gene, confirming the diagnosis of CMT4J.

The second patient, a 19-year-old man, started experiencing difficulty walking around the age of 2, as well as hearing difficulties and problems learning in school. More recently, he started having involuntary muscle contractions (dystonia) and weakness in his legs, further hindering his ability to walk.

As with the first patient, previous genetic tests on this teenager showed no mutations in PMP22 or in GJB1 (which causes CMTX). Several years after these analyses were done, WES identified a mutation in one copy of the LITAF gene, and the man was diagnosed with CMT1C.

The third patient was a 44-year-old man who visited a neurologist at the age of 17 due to muscle wasting in his legs. A diagnosis of CMT was made based on clinical presentation, but no underlying genetic cause was identified at the time.

Genetic testing done eight years before WES again found no PMP22 mutations. Ultimately, WES revealed the patient had a mutation in GJB1, confirming the diagnosis of CMTX.

“In three male patients suffering from polyneuropathy, three different types of CMT were identified using WES analysis,” the researchers wrote.

“In all three patients,” they added, “a long period of time had elapsed, and significant effort was spent, between their initial diagnostic investigations and the final diagnosis.”

These cases highlight the potential new genetic technologies, like WES, to diagnose genetic disorders like CMT that may be associated with mutations in different genes.

Researchers favored using a “simplified approach,” one in which WES is performed immediately after standard genetic tests for PMP22 identify no mutations in patient with symptoms that could be indicative of CMT.

“Nowadays, the novel diagnostic techniques, and specifically WES, have the power to reveal the cause of rare CMT subtypes, ending the diagnostic odyssey of the patients, and preventing unnecessary and potentially harmful treatments,” they concluded.