NEFH was first reported in relation to autosomal dominant amyotrophic lateral sclerosis in 1994 (Figlewicz et al., PMID: 7849698). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability (PMIDs: 27040688, 34518334, 7849698). Therefore, the following disease entities have been split into multiple disease entities, Charcot-Marie-Tooth disease, axonal, type 2CC (OMIM: 616924) and susceptibility to amyotrophic lateral sclerosis (OMIM: 105400). The split curation for autosomal dominant Charcot-Marie-Tooth disease, axonal, type 2CC has been curated separately. 20 variants (missense and large deletions) that have been reported in 20 probands in 13 publications (PMIDs: 29650794, 7849698, 9931323, 34511133, 8871580, 9875737, 21220648, 25299611, 28160950, 29411640, 31788332, 31475037, 32166880) are included in this curation. Additional variants in NEFH have been reported but were not scored in this curation due to high minor allele frequencies in population databases. Coding repeats in the KSP repeat region of NEFH affect phosphorylation and axonal integrity as the cross-bridge interaction with microtubules and other neurofilaments is destroyed, leading to cytoplasmic inclusions containing intermediate filament proteins. Missense variants residing mainly in the KSP repeat region have more recently been associated with ALS. Multiple screening and targeted sequencing panel studies have found that missense variants may modify risk for ALS. This gene-disease relationship is also supported by experimental evidence (an expression study). RT-PCR and western blot analysis showed an increase in transcript and protein levels of NEFH in sALS spinal cord (PMID:30029677). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on the meeting date March 23, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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