The p.(Leu97Ile) variant expands the genetic landscape of NEFL-associated Charcot-Marie-tooth neuropathies.

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INTRODUCTION: Charcot Marie Tooth neuropathies arise from diverse genetic disturbances that impair axonal structure or myelin integrity. Variants in NEFL, encoding the light chain of neurofilaments, represent a rare cause of CMT and may disrupt filament assembly, axonal transport, and cytoskeletal stability. Because NEFL variants are uncommon and phenotypes variable, the pathogenic relevance of individual substitutions is often difficult to determine. Here, we identified a previously unreported missense variant, p.(Leu97Ile), in three affected individuals. In two, a second variant, p.(Arg206Ser), was present in cis. We therefore aimed to investigate the pathogenic impact of this allele constellation using clinical, biochemical, and structural approaches. METHODS: Neurological examination, CMTNS scoring, and electrophysiological studies were performed. Exome sequencing established the genotype. Variant effects were assessed using serum biomarkers, in silico modelling and quantitative immunofluorescence of patient-derived fibroblasts. RESULTS: Patients showed differing clinical presentations, including moderate adult-onset neuropathy to severe early-onset disease and neuromuscular abnormalities in childhood. Neurophysiology revealed mixed features, and conduction slowing in the child supported classification within the CMT1F spectrum. All carriers exhibited elevated serum NfL; CK was increased in the adult patients. Descriptive biomarker differences between the patients were observed for GDF15, FGF21, Periaxin, and NCAM1. Fibroblasts displayed increased cytoplasmic NfL without altered nuclear metrics. Structural modelling predicted destabilizing effects of both substitutions, with the cis combination producing the strongest deviation. DISCUSSION: Integrated clinical, biochemical, and structural evidence support pathogenicity of p.(Leu97Ile) and suggest that p.(Arg206Ser) in cis augments its biological impact. These findings expand the genetic and phenotypic spectrum of NEFL-associated CMT1F.

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