Long-read sequencing (LRS), a method used by scientists to read large stretches of DNA at once, is helping CMTA-funded scientists identify the genetic causes of CMT previously undetected using standard testing methods.
The more we know about the genes that contribute to CMT types and subtypes, the better we can guide care, predict how the disease might progress, and move research closer to targeted treatments.
When standard genetic testing, such as short-read sequencing, falls short of answers, Andrea Cortese, MD, PhD, and his team at University College London are using long-read sequencing to identify complex gene patterns and regions in the genome related to CMT.
With a $210,000 research grant from CMTA, Dr. Corteses’ team reanalyzed short-read sequencing (SRS) data from more than 1,400 people with CMT, applying updated tools and detailed clinical review to increase the number of confirmed genetic diagnoses. This effort helped define a group of 150 unsolved cases for LRS.
LRS can read much larger stretches of DNA at once, allowing scientists to detect mutations that are too complex, repetitive, or hidden for standard methods to find. Among these are CGG repeat expansions, a type of mutation that repeats a small section of a gene so many times that it interferes with the function of nearby genes. These changes cannot be seen by standard genetic testing, but LRS can detect them clearly.
Why Do CGG Repeats Matter for CMT?
In our DNA, the three-letter sequence CGG sometimes repeats over and over again. A small number of repeats is normal, but when that section repeats too many times, it expands too far and disrupts how nearby genes function. These CGG repeat expansions are known to cause several neurological diseases, and scientists are now studying how they might also play a role in CMT.
Until recently, these CGG expansions were not considered a cause of CMT because SRS cannot detect them. SRS cannot read through long repetitive stretches of DNA, but LRS can, and that is why this research is so important in CMT.
Results From Long-Read Sequencing Are
With LRS, Dr. Cortese’s team is uncovering answers that standard testing has missed for years. Their work has already confirmed that CGG repeat expansions can play a role in CMT, leading to seven community members receiving long-awaited genetic confirmations. Their mutations were found in genes already known in CMT but had been missed by standard genetic testing (AARS, BSCL2, DNAJB2, HSPB1, MYH7, NARS1, and SCN9A).
Using LRS, the team also identified previously hidden mutations in the SORD gene, which are challenging to detect with standard testing. These results show how long-read technology can solve CMT cases that have remained unconfirmed for years.
The team’s research further contributed to the international collaboration that verified mutations in the KCTD11 gene as the cause of a newly identified rare subtype, Recessive Intermediate CMT E (CMTRIE).
Together, these advances show how LRS is closing the diagnostic gap and expanding the known genetic landscape of CMT, providing much-needed answers for community members.
Why It Matters
For thousands of people in the CMT community still searching for a genetic diagnosis, LRS is changing what’s possible. Each gene discovery brings science closer to understanding how CMT begins, paving the way for precision diagnostics and, eventually, treatments and a cure.
