An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families
Masahiro Ando1, Yujiro Higuchi1, Yuji Okamoto1
1Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Background And Aims:
Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan.
Methods:
We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA).
Results:
We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect.
Interpretation:
This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.
Insights
A founder mutation in the neurofilament heavy (NEFH) gene was identified in Japanese families with Charcot-Marie-Tooth disease (CMT) and spinal muscular atrophy (SMA). This discovery expands the known clinical and genetic spectrum of NEFH-related neuromuscular disorders.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Mutations in neurofilament genes are associated with neuromuscular disorders.
- The neurofilament heavy (NEFH) gene, identified in 2016, causes Charcot-Marie-Tooth disease type 2CC (CMT2CC) via a toxic gain of function mechanism involving amyloidogenic element aggregation.
- The clinical and genetic spectrum of NEFH-related disorders in Japan remains largely undefined.
Purpose of the Study:
- To investigate the NEFH gene variants in Japanese patients with neuromuscular disorders.
- To clarify the clinical and genetic spectrum of NEFH-related diseases in Japan.
- To identify potential founder mutations within the Japanese population.
Main Methods:
- Analysis of all NEFH gene variants from in-house whole-exome sequencing data of Japanese patients.
- Inclusion of patients diagnosed with Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA).
- Haplotype analysis to investigate potential founder effects.
Main Results:
- A c.3017dup (p.Pro1007Alafs*56) variant in NEFH was identified in three CMT families and one SMA family.
- Clinical presentations included typical peripheral neuropathies, pyramidal signs in one CMT patient, and severe weakness in triceps brachii and quadriceps femoris in SMA patients.
- All affected families were from Kagoshima Prefecture, Japan, with haplotype analysis strongly suggesting a founder effect.
Conclusions:
- This study reports the first founder mutation in the NEFH gene.
- The observed clinical diversity, encompassing CMT with and without pyramidal signs, and SMA, indicates involvement of peripheral nerves, anterior horn cells, or both.
- These findings significantly broaden the phenotypic spectrum associated with NEFH-related disorders.
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