New Gene Modifiers May Explain Disease Variability in CMT1A, Study Suggests

A group of potential gene modifiers have been found that may explain the reason why patients with Charcot-Marie-Tooth disease type 1A (CMT1A) who share the same genetic mutation experience different symptoms at varying degrees of severity, a study reports.

The study, “Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study,” was published in the Journal of Neuromuscular Diseases.

Charcot-Marie-Tooth (CMT) is the most common heritable disease that affects the peripheral nervous system — the network of nerves responsible for controlling movement and sensation in the limbs. The disease can be caused by different genetic mutations and manifest at various ages, depending on its particular type and subtype.

CMT1A is normally associated with genetic mutations in the PMP22 gene, which provides instructions to make a protein called peripheral myelin protein 22 (PMP22), a component of myelin, the fatty substance that insulates nerve fibers and is essential for the transmission of electrical signals between neurons.

“Patients with CMT1A show typical clinical features of CMT with both motor and sensory involvement, but the exact phenotypic [symptom] presentation and disease severity often vary greatly. The cause of the clinical variability is largely unknown,” the investigators wrote.

One of the hypotheses that might explain the high degree of variability in CMT1A is the presence of gene modifiers — genes located in a different region that may affect the activity and function of the gene involved in the disease, in this case, PMP22.

To explore this possibility, a group of researchers from the University of Miami and their collaborators isolated DNA samples from 971 CMT1A patients and performed genetic screenings on more than 600,000 genomic markers to look for alterations in their sequence.

They then performed a case-only genome-wide association study (GWAS) in a subgroup of 644 CMT1A patients of European ancestry to look for possible associations between the findings from the genetic analyses and patients’ clinical outcomes. GWAS are studies based on a method that scans the genome — all of the genes present in our DNA — looking for specific types of genetic alterations found more frequently in people with a particular disease.

Researchers analyzed a total of 14 different clinical outcomes, which included overall disease severity, motor symptoms, sensory symptoms, muscle strength, presence of foot deformities, scoliosis, and hearing loss.

Results showed that four different clusters of single nucleotide polymorphisms (SNPs), which correspond to variations in a single nucleotide (the building blocks of DNA) in the DNA sequence of a gene, were strongly linked to four different clinical outcomes:

• Lead SNP rs4713376 on chromosome 6 was linked to difficulty eating using utensils.
• Lead SNP rs7720606 on chromosome 5 was linked to hearing loss.
• Lead SNP rs17629990 on chromosome 4 was linked to loss of feeling.
• Lead SNP rs12137595 on chromosome 1 was linked to overall disease severity (assessed by the CMT neuropathy score).

Scientists are confident that genes located near these clusters may be promising gene modifier candidates that ought to be investigated in future studies.

“This is still a high-level statistical exploration and the benefit for individual patients is not yet fully understood. In the best-case scenario, we will be able to use such modifier genetic information to predict more precisely the natural course of disease in a single person,” Stephan Züchner, MD, PhD, of the Department of Human Genetics and Hussman Institute for Human Genomics of the University of Miami and lead author of the study, said in a press release.

“As new genetic therapies and small molecular screening technologies mature, such targets can be exploited much faster,” he added.

In addition, the researchers noted that more genomic studies exploring these associations in CMT1A patients of European origin and other ancestries are needed to fully understand the degree of association between genetic factors and disease presentation.

They also anticipate that these approaches could be applied to other genetic disorders that tend to have a high degree of clinical variability.