NEFL was first gene reported in relation to autosomal dominant Charcot-Marie-Tooth disease in 2000 (Mersiyanova et al., PMID: 10841809). Based on the literature we differentiate between autosomal dominant NEFL CMT (MONDO:0015626), autosomal recessive NEFL CMT (MONDO:0018993). For autosomal dominant NEFL CMT, five variants (missense) that have been reported in 9 probands in 7 publications (PMIDs: 10841809, 28501821, 11220745, 12566280, 18758688, 14733962, 12477167) are included in this curation. The p.Pro22(Thr/Arg/Ser), p.Pro8(Leu/GlnArg) and the p.Asn98(Ser/Thr) are considered hotspot variants. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be a gain-of-function due to misdistribution and aggregate formations of NFL. This gene-disease relationship is also supported by functional experimental evidence in controls, patients, and animal models (PMIDs: 25552649, 28654681, 17881652, 9388258, 9398473, 34485306, 31715019). In-vitro functional studies for all described variants depict disruptions in NF network and aggregation of NFL. In summary, NEFL is definitively associated with autosomal dominant axonal Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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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