NEFH

Inheritance Pattern: AD

Disease ID:MONDO:0014836

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014836

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

*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).

Inheritance Pattern: AD

Disease ID:MONDO:0014836

Submitter: ClinGen

NEFH was first reported to be associated with autosomal dominant Charcot-Marie-Tooth disease type 2 in 2016 (Rebelo et al., PMID:27040688). This gene has also been implicated as a risk factor in ALS. NEFH encodes for the neurofilament heavy chain, a key component of neurofilaments, essential for the formation of cytoskeleton in neurons. Clinical features of patients with NEFH mutations include sensorimotor axonal neuropathy mainly characterized by distal lower limbs motor deficit with early and prominent involvement of proximal hip muscles. Additional common features include muscle cramps and increased creatine kinase level. All reported cases have frameshift mutations that cluster at the c-terminus end of the protein. Mutations result in loss of the stop codon and translation of the 3’-UTR. NEFH mutants carry a sequence extension of 45 extra amino acids, containing an amyloidogenic motif referred as cryptic amyloidogenic element of the 3’-UTR (CAE). This type of variant has been reported in 4 additional publications (PMIDs: 28709447, 28544463, 29587262, 30992180). NEFH physically interacts with NEFL, also a known CMT gene, forming neurofilament structures. The NEFH knockout mouse model showed diminished calibers of large myelinated axons in both central and peripheral nervous systems (Eder et at, PMID: 976343). Expression of frameshift mutants in cultured cells resulted in accumulation of prominent perinuclear aggregates, disrupted neurofilaments structures and cell toxicity (PMID:27040688). Expression of NEFH mutants in zebrafish resulted in abnormal motor neurons with truncated axons. A zebrafish rescue experiment showed that the WT human NEFH mRNA can rescue the morpholino injected fish, however, NEFH frameshift mutants were not able to rescue the phenotype (PMID:28544463). Expression of CMT-NEFH mutations in chick embryos resulted in neurofilament aggregates in the soma of neurons leading to neuronal cell death. Aggregates stain positive for activated caspase 3 and the autophagy marker p62 (Jacquier et al., PMID: 28709447). In summary, NEFH genetic and functional evidence was classified as DEFINITIVE.