Identical NEFH Mutation Suggests Common Ancestry in 4 Families

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by Lindsey Shapiro PhD |

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An NEFH gene mutation was identified in three unrelated Japanese families with Charcot-Marie-Tooth (CMT) disease and one family with spinal muscular atrophy (SMA), suggesting they share a common ancestor, a recent study proposes. 

The study marks the first case of CMT type 2CC (CMT2CC) identified in Japan, and is the first NEFH mutation to be associated with a common ancestor, or founder, across multiple patients. 

To our best knowledge, this is not only the first report of CMT2CC in Japan, but also the original founder mutation found in the NEFH gene worldwide,” the research team wrote.

The study, “An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families,” was published in the Journal of Human Genetics.  

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NEFH is responsible for making neurofilament heavy chain, a structural protein involved in the growth and function of axons, or nerve cell fibers.

Mutations in NEFH cause CMT2CC, a rare CMT subtype that clinically resembles SMA. Both diseases are characterized by muscle weakness and motor disturbances. SMA is usually caused by mutations in the SMN1 gene, but in rare cases can be associated with other genes.

Researchers used genetic sequencing to look for NEFH mutations among 804 patients, including those with CMT and SMA, for whom a disease-causing mutation had not been identified between 2007 and 2020.

Four unrelated families from the same region in Japan were found to have an identical NEFH mutation. Based on their analysis, the researchers determined the mutation was likely pathogenic, or disease-causing.

The mutation, called c.3017dup, was inherited in an autosomal dominant manner, meaning a person only has to inherit it from one parent to exhibit symptoms.

All patients with the mutation had normal development in childhood, with symptoms emerging in adulthood.

Members of three families were diagnosed with CMT. Most had muscle weakness in the lower arms and legs that eventually affected motor ability. Sensory disturbances, such as numbness or tingling in their muscles, all suggesting peripheral neuropathy, or damage to the nerves outside of the brain and spinal cord.

One person also showed signs that the pyramidal tract — the nerves running from the brain and spinal cord — was involved. This patient was diagnosed with hereditary motor and sensory neuropathy-V, a type of CMT.

Members of the family diagnosed with SMA showed more proximal muscle weakness, affecting the arm and leg muscles closer to the body.

Patients from all four families had high blood levels of creatine kinase, indicating muscle damage.

The researchers were unable to identify how a single mutation could cause a range of symptoms and different diagnoses.

“The cause of clinical diversity by the same NEFHmutation is unclear,” they wrote.

Although the four families were not related, the team found that the mutation was embedded in a larger stretch of DNA that was identical across all the members.

This happens when a group of people descend from the same ancestors, with all inheriting that same stretch of DNA from a common ancestor, according to the researchers. This is called a founder effect, and the mutation is called a founder mutation.

“It is very likely that this [mutation] originates from a common Japanese ancestor,” the researchers wrote.

This mutation has been reported in a U.K. family. If that family showed the same identical stretch of DNA, it’s likely to have also originated from the same ancestor, the researchers noted.

Several NEFH mutations have now been described, and many occur in the same part of the gene as the mutation reported in this study.

With this case report, CMT2CC has been reported across families of French, Chinese, Australian, Italian, Greek, and Japanese ancestry.