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.
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