The p.(Leu97Ile) variant expands the genetic landscape of NEFL -associated Charcot–Marie-tooth neuropathies
Year: 2026
Type: article
Study design: Case Report
Abstract: 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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddag028
Institutions: BG University Hospital Bergmannsheil Bochum, Ruhr University Bochum, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, University of Duisburg-Essen, Children's Hospital of Eastern Ontario, Medical Genetics Center, Ludwig-Maximilians-Universität München, University of Cambridge, University of Ottawa, Ottawa Hospital, uOttawa Brain and Mind Research Institute
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: Muscular Dystrophy UK, LifeArc, UK Research and Innovation, Government of Canada, National Institute for Health and Care Research, Department of Health and Social Care, Ataxia UK, European Commission, Rosetrees Trust, Deutsche Forschungsgemeinschaft, Canada Research Chairs, Canada First Research Excellence Fund, HORIZON EUROPE Framework Programme, Canadian Institutes of Health Research, Medical Research Council, European Regional Development Fund, NIHR Cambridge Biomedical Research Centre
Awards: G1014246945, G1189670905, G1254555223, G1366525601, G1443089283, G1914228270, G1977987814, G2228563315, G2235045993, G2266534423, G2375541257, G2493601830, G2537968379, G2614133680, G2763881574, G2767849847, G2920001861, G3353928523, G3513744673, G3522602058, G3602036837, G3648556220, G3777639711, G3852724337, G3864338403, G3906216459, G4166310527, G4311321735, G4395209027, G4466902010, G4682684196, G4753630297, G4785284928, G4905629147, G5097141464, G5141098744, G5360572808, G5594368681, G5699055735, Targeting the cellular metabolism to treat tissue-specific mitochondrial diseases, Brain-Heart Interconnectome, MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases, NMD4C: the neuromuscular network for Canada, G6401263891, G6457627045, G6701827816, G6746949437, G6805063602, G692795203, G7061099144, G7076316076, G7100031956, G724433139, G7295870680, G7402325741, GRK 2578: Einfluss von Genotoxinen auf die Differenzierungseffizienz muriner und humaner Stamm und Progenitorzellen sowie die Funktionalität von daraus abgeleiteten differenzierten Zelltypen, G7570539936, G7641387588, G7726061498, G7742460208, G7798797775, G7910070384, Probing Star Formation and Galaxy Evolution with Gamma-Ray Bursts, G8181187624, Accelerating drug repurposing for rare neurological, neurometabolic and neuromuscular disorders by exploiting SIMilarities in clinical and molecular PATHology, G8460769577, G8575920825, Novel therapeutic approaches to target GNE Myopathy, G864407001, G8875776916, G902999079
OpenAlex ID: W7155154392